https://proteopedia.org/api.php?action=feedcontributions&feedformat=atom&user=Laurine+GrimandiProteopedia - User contributions [en]2026-10-09T06:02:20ZUser contributionsMediaWiki 1.43.8https://proteopedia.org/index.php?title=Sandbox_Reserved_1098&diff=3505776Sandbox Reserved 10982022-01-21T22:21:23Z<p>Laurine Grimandi: </p>
<hr />
<div>{{Sandbox_ESBS_2019}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==6HMM== <br />
<StructureSection load='6hmm' size='340' side='right' caption='[[6hmm]]' scene=''><br />
The <scene name='82/829351/6hmm/2'>6HMM protein</scene> is a human[[ poly (ADP-ribose) glycohydrolase]].It is the major enzyme responsible for the catabolism of poly (ADP-ribose), a reversible covalent-modifier of chromosomal proteins. The protein is found in many tissues and may be subject to proteolysis generating smaller, active products.<br />
This protein is only present when the DNA is damaged. It influences the damaged chromatin through a derepression of a gene promoter. Consequently this protein is quite interesting for biotechnological applications. Indeed, knowing the different pathways and protein interactions leading to DNA damage repair is a meaningful goal in research especially in new cancer therapies. <br />
<br />
<br />
== Catabolism of poly (ADP-ribose) ==<br />
<br />
This protein has four principal domains on a <scene name='82/829351/Single_chain/1'>single peptide chain</scene>: an A-domain, a catalytic domain and two substrate binding domains. <br />
The first 456 amino acids of the peptide chain form the <scene name='82/829351/A_domain/1'>A-domain</scene>. Then, from the 610th to the 795th amino acids the <scene name='82/829351/Catalytic_domain/1'>catalytic domain</scene> can be found. This catalytic domain can bind to other proteins with <scene name='82/829351/Substrat_-_catalytic_domain/1'>two amino acids</scene> (the 726th and 727th amino acids). Next, <scene name='82/829351/Subtrat_jonction_domain_2/1'>the second substrate binding domain</scene> is located from the 869th to the 874th amino acid.<br />
As such, most of the amino acids form the A-domain and the catalytic domain and only a few amino acids (8 a.a) make links with other proteins. Moreover, the ligand 7JB can bind the protein on the <scene name='82/829351/Liason_7jb/1'>754, 758, 792 and 795 amino acids</scene>. These amino acids are located on a helix and on a beta sheet. There is the <scene name='82/829351/Distritbution_domain/1'>following</scene> amino acid distribution [http://www.uniprot.org/uniprot/Q86W56].<br />
<br />
The protein <scene name='82/829351/Parg/1'>PARG</scene> folds into an ADP-ribose-binding macro domain with an N-terminal extension. It also consists of a diphosphate-binding loop on one side of an ADP-ribose binding cavity. On the other side there are several amino acids matching to the specific <scene name='82/829351/Parg/1'>PARG</scene> signature sequence. <br />
In the macro domain fold, a loop is inserted to welcome the Glu115 side chain protecting the active site of the <scene name='82/829351/Parg/1'>PARG</scene> protein. This loop gives <scene name='82/829351/Parg/1'>PARG</scene> the ability to hydrolyze PAR. The <scene name='82/829351/Parg_active_site/1'>hydrolysis of PAR happens in PARG catalytic domain</scene>. (PAR is represented here in pink).<br />
<br />
<br />
<br />
== Post-translational modifications ==<br />
<br />
The protein is a complex composed of the [[ poly (ADP-ribose) glycohydrolase]] (PARG) and the anthraquinone PDD00013907. The Poly(ADP-ribose)glycohydrolase can interact with either [[PCNA]] or [[NUDT5]], this gives various possible functions to the protein. When this protein binds with NUDT5 it can remodel chromatin for example. The post-translational modifications of the PAR protein (poly ADP-ribose) are important for DNA stability. <br />
PDD00013907 is, as already stated, an anthraquinone which is a polycyclic aromatic hydrocarbon usually used in biopesticides as a pest repellant. Here it is considered as a free <scene name='82/829351/7jb/1'>ligand</scene> (of identification number on PDB: 7JB) that can bind to the <scene name='82/829351/Parg/1'>PARG</scene> creating the<scene name='82/829351/Complex/1'> protein complex 6HMM</scene>. <br />
<br />
There are several possible post-translational modifications to stabilize DNA. Most commonly there would be phosphorylation, acetylation or methylation <ref>PMID: 21037856</ref>.<br />
Another post-translational modification concerning the <scene name='82/829351/6hmm/2'>6HMM protein</scene> is made on the poly(ADP-ribose) protein (PAR). PAR is composed of a repetition of ADP-ribose units linked through glycosidic ribose-ribose bonds <ref>doi: 10.1038/nature10404</ref>. This allows the repair of single-strand breaks on DNA <ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792.">DOI: 10.1021/acs.jmedchem.8b01407</ref>. The Poly (ADP-ribose) polymerase (PARP), more specifically the subtype [http://www.uniprot.org/uniprot/P09874 PARP1], will recognize and will bind to the single-stranded break on the DNA. It will then autophosphorylate and form PAR chains. These will recruit other repair proteins to the site. The role of <scene name='82/829351/Parg/1'>PARG</scene> is the hydrolyzation of the specific ribose-ribose bonds present in PAR which leads to its degradation and as such the reparation cycle will be finished<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/>.<br />
<br />
The anthraquinone PDD00013907 is a weakly active and cytotoxic anthraquinone 8a acting as a free ligand binding in the ADP-ribose binding site of the <scene name='82/829351/Parg/1'>PARG</scene>. This PDD00013907 should lead to the inhibition of <scene name='82/829351/Parg/1'>PARG</scene>, which is of interest in the search of novel cancer therapies <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. <br />
<br />
<br />
<br />
== Diseases and Treatment ==<br />
<br />
Due to the function of the protein poly (ADP-ribose) glycohydrolase <scene name='82/829351/Parg/1'>PARG</scene> to be part of post-translational processes of DNA damage repair it could be used for new treatments in cancer therapy or for ther diseases. In cancer cells the rate of DNA damage is most probably higher than in normal cells. This could result from the considerably raised stress levels. A deficiency of <scene name='82/829351/Parg/1'>PARG</scene> results in the cessing of the cell cycle and the following cell death<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/><ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. Consequently, the inhibition of <scene name='82/829351/Parg/1'>PARG</scene> might be a solution on how to destroy tumor cells, for example.<br />
<br />
The PAR protein is a potential target in drug discovery as there are no close homologues of <scene name='82/829351/Parg/1'>PARG</scene>. That’s why there has already been a lot of research concerning novel treatments.<br />
<br />
The goal of searched therapeutics is to find a way to get the protein <scene name='82/829351/Parg/1'>PARG</scene> into a complex that is acting similar to the <scene name='82/829351/Parg/1'>6HMM complex</scene>.Indeed the protein in complex with the anthraquinone does not work properly anymore [http://www.rcsb.org/structure/6HMM], the described complex shows how an inhibited <scene name='82/829351/Parg/1'>PARG</scene> might act in the cell. For now, the research for anthraquinone as inhibitor has stopped as it is cytotoxic for the cell<ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>.<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Laurine Grimandihttps://proteopedia.org/index.php?title=Sandbox_Reserved_1098&diff=3505775Sandbox Reserved 10982022-01-21T22:18:01Z<p>Laurine Grimandi: </p>
<hr />
<div>{{Sandbox_ESBS_2019}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==6HMM== <br />
<StructureSection load='6hmm' size='340' side='right' caption='[[6hmm]]' scene=''><br />
The <scene name='82/829351/6hmm/2'>6HMM protein</scene> is a human[[ poly (ADP-ribose) glycohydrolase]].It is the major enzyme responsible for the catabolism of poly (ADP-ribose), a reversible covalent-modifier of chromosomal proteins. The protein is found in many tissues and may be subject to proteolysis generating smaller, active products.<br />
This protein is only present when the DNA is damaged. It influences the damaged chromatin through a derepression of a gene promoter. Consequently this protein is quite interesting for biotechnological applications. Indeed, knowing the different pathways and protein interactions leading to DNA damage repair is a meaningful goal in research especially in new cancer therapies. <br />
<br />
<br />
== Catabolism of poly (ADP-ribose) ==<br />
<br />
This protein has four principal domains on a <scene name='82/829351/Single_chain/1'>single peptide chain</scene>: an A-domain, a catalytic domain and two substrate binding domains. <br />
The first 456 amino acids of the peptide chain form the <scene name='82/829351/A_domain/1'>A-domain</scene>. Then, from the 610th to the 795th amino acids the <scene name='82/829351/Catalytic_domain/1'>catalytic domain</scene> can be found. This catalytic domain can bind to other proteins with <scene name='82/829351/Substrat_-_catalytic_domain/1'>two amino acids</scene> (the 726th and 727th amino acids). Next, <scene name='82/829351/Subtrat_jonction_domain_2/1'>the second substrate binding domain</scene> is located from the 869th to the 874th amino acid.<br />
As such, most of the amino acids form the A-domain and the catalytic domain and only a few amino acids (8 a.a) make links with other proteins. Moreover, the ligand 7JB can bind the protein on the <scene name='82/829351/Liason_7jb/1'>754, 758, 792 and 795 amino acids</scene>. These amino acids are located on a helix and on a beta sheet. There is the <scene name='82/829351/Distritbution_domain/1'>following</scene> amino acid distribution [http://www.uniprot.org/uniprot/Q86W56].<br />
<br />
The protein <scene name='82/829351/Parg/1'>PARG</scene> folds into an ADP-ribose-binding macro domain with an N-terminal extension. It also consists of a diphosphate-binding loop on one side of an ADP-ribose binding cavity. On the other side there are several amino acids matching to the specific <scene name='82/829351/Parg/1'>PARG</scene> signature sequence. <br />
In the macro domain fold, a loop is inserted to welcome the Glu115 side chain protecting the active site of the <scene name='82/829351/Parg/1'>PARG</scene> protein. This loop gives <scene name='82/829351/Parg/1'>PARG</scene> the ability to hydrolyze PAR. The <scene name='82/829351/Parg_active_site/1'>hydrolysis of PAR happens in PARG catalytic domain</scene>. (PAR is represented here in pink).<br />
<br />
<br />
<br />
== Post-translational modifications ==<br />
<br />
The protein is a complex composed of the [[ poly (ADP-ribose) glycohydrolase]] (PARG) and the anthraquinone PDD00013907. The Poly(ADP-ribose)glycohydrolase can interact with either [[PCNA]] or [[NUDT5]], this gives various possible functions to the protein. When this protein binds with NUDT5 it can remodel chromatin for example [http://www.uniprot.org/uniprot/Q86W56]. The post-translational modifications of the PAR protein (poly ADP-ribose) are important for DNA stability. <br />
PDD00013907 is, as already stated, an anthraquinone which is a polycyclic aromatic hydrocarbon usually used in biopesticides as a pest repellant. Here it is considered as a free <scene name='82/829351/7jb/1'>ligand</scene> (of identification number on PDB: 7JB) that can bind to the <scene name='82/829351/Parg/1'>PARG</scene> creating the<scene name='82/829351/Complex/1'> protein complex 6HMM</scene>. <br />
<br />
There are several possible post-translational modifications to stabilize DNA. Most commonly there would be phosphorylation, acetylation or methylation <ref>PMID: 21037856</ref>.<br />
Another post-translational modification concerning the <scene name='82/829351/6hmm/2'>6HMM protein</scene> is made on the poly(ADP-ribose) protein (PAR). PAR is composed of a repetition of ADP-ribose units linked through glycosidic ribose-ribose bonds <ref>doi: 10.1038/nature10404</ref>. This allows the repair of single-strand breaks on DNA <ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792.">DOI: 10.1021/acs.jmedchem.8b01407</ref>. The Poly (ADP-ribose) polymerase (PARP), more specifically the subtype [http://www.uniprot.org/uniprot/P09874 PARP1], will recognize and will bind to the single-stranded break on the DNA. It will then autophosphorylate and form PAR chains. These will recruit other repair proteins to the site. The role of <scene name='82/829351/Parg/1'>PARG</scene> is the hydrolyzation of the specific ribose-ribose bonds present in PAR which leads to its degradation and as such the reparation cycle will be finished<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/>.<br />
<br />
The anthraquinone PDD00013907 is a weakly active and cytotoxic anthraquinone 8a acting as a free ligand binding in the ADP-ribose binding site of the <scene name='82/829351/Parg/1'>PARG</scene>. This PDD00013907 should lead to the inhibition of <scene name='82/829351/Parg/1'>PARG</scene>, which is of interest in the search of novel cancer therapies <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. <br />
<br />
<br />
<br />
== Diseases and Treatment ==<br />
<br />
Due to the function of the protein poly (ADP-ribose) glycohydrolase <scene name='82/829351/Parg/1'>PARG</scene> to be part of post-translational processes of DNA damage repair it could be used for new treatments in cancer therapy or for ther diseases. In cancer cells the rate of DNA damage is most probably higher than in normal cells. This could result from the considerably raised stress levels. A deficiency of <scene name='82/829351/Parg/1'>PARG</scene> results in the cessing of the cell cycle and the following cell death<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/><ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. Consequently, the inhibition of <scene name='82/829351/Parg/1'>PARG</scene> might be a solution on how to destroy tumor cells, for example.<br />
<br />
The PAR protein is a potential target in drug discovery as there are no close homologues of <scene name='82/829351/Parg/1'>PARG</scene>. That’s why there has already been a lot of research concerning novel treatments.<br />
<br />
The goal of searched therapeutics is to find a way to get the protein <scene name='82/829351/Parg/1'>PARG</scene> into a complex that is acting similar to the <scene name='82/829351/Parg/1'>6HMM complex</scene>.Indeed the protein in complex with the anthraquinone does not work properly anymore [http://www.rcsb.org/structure/6HMM], the described complex shows how an inhibited <scene name='82/829351/Parg/1'>PARG</scene> might act in the cell. For now, the research for anthraquinone as inhibitor has stopped as it is cytotoxic for the cell<ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>.<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Laurine Grimandihttps://proteopedia.org/index.php?title=Sandbox_Reserved_1098&diff=3505774Sandbox Reserved 10982022-01-21T22:08:48Z<p>Laurine Grimandi: </p>
<hr />
<div>{{Sandbox_ESBS_2019}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==6HMM== <br />
<StructureSection load='6hmm' size='340' side='right' caption='[[6hmm]]' scene=''><br />
The <scene name='82/829351/6hmm/2'>6HMM protein</scene> is a human[[ poly (ADP-ribose) glycohydrolase]].It is the major enzyme responsible for the catabolism of poly (ADP-ribose), a reversible covalent-modifier of chromosomal proteins. The protein is found in many tissues and may be subject to proteolysis generating smaller, active products.<br />
This protein is only present when the DNA is damaged. It influences the damaged chromatin through a derepression of a gene promoter. Consequently this protein is quite interesting for biotechnological applications. Indeed, knowing the different pathways and protein interactions leading to DNA damage repair is a meaningful goal in research especially in new cancer therapies. <br />
<br />
<br />
== Catabolism of poly (ADP-ribose) ==<br />
<br />
This protein has four principal domains on a <scene name='82/829351/Single_chain/1'>single peptide chain</scene>: an A-domain, a catalytic domain and two substrate binding domains[http://www.uniprot.org/uniprot/Q86W56]. <br />
The first 456 amino acids of the peptide chain form the <scene name='82/829351/A_domain/1'>A-domain</scene>. Then, from the 610th to the 795th amino acids the <scene name='82/829351/Catalytic_domain/1'>catalytic domain</scene> can be found. This catalytic domain can bind to other proteins with <scene name='82/829351/Substrat_-_catalytic_domain/1'>two amino acids</scene> (the 726th and 727th amino acids). Next, <scene name='82/829351/Subtrat_jonction_domain_2/1'>the second substrate binding domain</scene> is located from the 869th to the 874th amino acid. [http://www.uniprot.org/uniprot/Q86W56]<br />
As such, most of the amino acids form the A-domain and the catalytic domain and only a few amino acids (8 a.a) make links with other proteins. Moreover, the ligand 7JB can bind the protein on the <scene name='82/829351/Liason_7jb/1'>754, 758, 792 and 795 amino acids</scene>. These amino acids are located on a helix and on a beta sheet. [http://www.rcsb.org/pdb/explore/remediatedSequence.do?structureId=6HMM]. There is the <scene name='82/829351/Distritbution_domain/1'>following</scene> amino acid distribution.<br />
<br />
The protein <scene name='82/829351/Parg/1'>PARG</scene> folds into an ADP-ribose-binding macro domain with an N-terminal extension. It also consists of a diphosphate-binding loop on one side of an ADP-ribose binding cavity. On the other side there are several amino acids matching to the specific <scene name='82/829351/Parg/1'>PARG</scene> signature sequence. <br />
In the macro domain fold, a loop is inserted to welcome the Glu115 side chain protecting the active site of the <scene name='82/829351/Parg/1'>PARG</scene> protein. This loop gives <scene name='82/829351/Parg/1'>PARG</scene> the ability to hydrolyze PAR. The <scene name='82/829351/Parg_active_site/1'>hydrolysis of PAR happens in PARG catalytic domain</scene>. (PAR is represented here in pink).<br />
<br />
<br />
<br />
== Post-translational modifications ==<br />
<br />
The protein is a complex composed of the [[ poly (ADP-ribose) glycohydrolase]] (PARG) and the anthraquinone PDD00013907. The Poly(ADP-ribose)glycohydrolase can interact with either [[PCNA]] or [[NUDT5]], this gives various possible functions to the protein. When this protein binds with NUDT5 it can remodel chromatin for example [http://www.uniprot.org/uniprot/Q86W56]. The post-translational modifications of the PAR protein (poly ADP-ribose) are important for DNA stability. <br />
PDD00013907 is, as already stated, an anthraquinone which is a polycyclic aromatic hydrocarbon usually used in biopesticides as a pest repellant. Here it is considered as a free <scene name='82/829351/7jb/1'>ligand</scene> (of identification number on PDB: 7JB) that can bind to the <scene name='82/829351/Parg/1'>PARG</scene> creating the<scene name='82/829351/Complex/1'> protein complex 6HMM</scene>. <br />
<br />
There are several possible post-translational modifications to stabilize DNA. Most commonly there would be phosphorylation, acetylation or methylation <ref>PMID: 21037856</ref>.<br />
Another post-translational modification concerning the <scene name='82/829351/6hmm/2'>6HMM protein</scene> is made on the poly(ADP-ribose) protein (PAR). PAR is composed of a repetition of ADP-ribose units linked through glycosidic ribose-ribose bonds <ref>doi: 10.1038/nature10404</ref>. This allows the repair of single-strand breaks on DNA <ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792.">DOI: 10.1021/acs.jmedchem.8b01407</ref>. The Poly (ADP-ribose) polymerase (PARP), more specifically the subtype [http://www.uniprot.org/uniprot/P09874 PARP1], will recognize and will bind to the single-stranded break on the DNA. It will then autophosphorylate and form PAR chains. These will recruit other repair proteins to the site. The role of <scene name='82/829351/Parg/1'>PARG</scene> is the hydrolyzation of the specific ribose-ribose bonds present in PAR which leads to its degradation and as such the reparation cycle will be finished<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/>.<br />
<br />
The anthraquinone PDD00013907 is a weakly active and cytotoxic anthraquinone 8a acting as a free ligand binding in the ADP-ribose binding site of the <scene name='82/829351/Parg/1'>PARG</scene>. This PDD00013907 should lead to the inhibition of <scene name='82/829351/Parg/1'>PARG</scene>, which is of interest in the search of novel cancer therapies <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. <br />
<br />
<br />
<br />
== Diseases and Treatment ==<br />
<br />
Due to the function of the protein poly (ADP-ribose) glycohydrolase <scene name='82/829351/Parg/1'>PARG</scene> to be part of post-translational processes of DNA damage repair it could be used for new treatments in cancer therapy or for ther diseases. In cancer cells the rate of DNA damage is most probably higher than in normal cells. This could result from the considerably raised stress levels. A deficiency of <scene name='82/829351/Parg/1'>PARG</scene> results in the cessing of the cell cycle and the following cell death<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/><ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. Consequently, the inhibition of <scene name='82/829351/Parg/1'>PARG</scene> might be a solution on how to destroy tumor cells, for example.<br />
<br />
The PAR protein is a potential target in drug discovery as there are no close homologues of <scene name='82/829351/Parg/1'>PARG</scene>. That’s why there has already been a lot of research concerning novel treatments.<br />
<br />
The goal of searched therapeutics is to find a way to get the protein <scene name='82/829351/Parg/1'>PARG</scene> into a complex that is acting similar to the <scene name='82/829351/Parg/1'>6HMM complex</scene>.Indeed the protein in complex with the anthraquinone does not work properly anymore [http://www.rcsb.org/structure/6HMM], the described complex shows how an inhibited <scene name='82/829351/Parg/1'>PARG</scene> might act in the cell. For now, the research for anthraquinone as inhibitor has stopped as it is cytotoxic for the cell<ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>.<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Laurine Grimandihttps://proteopedia.org/index.php?title=Sandbox_Reserved_1098&diff=3505773Sandbox Reserved 10982022-01-21T22:06:01Z<p>Laurine Grimandi: </p>
<hr />
<div>{{Sandbox_ESBS_2019}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==6HMM== <br />
<StructureSection load='6hmm' size='340' side='right' caption='[[6hmm]]' scene=''><br />
The <scene name='82/829351/6hmm/2'>6HMM protein</scene> is a human[[ poly (ADP-ribose) glycohydrolase]].It is the major enzyme responsible for the catabolism of poly (ADP-ribose), a reversible covalent-modifier of chromosomal proteins. The protein is found in many tissues and may be subject to proteolysis generating smaller, active products.<br />
This protein is only present when the DNA is damaged. It influences the damaged chromatin through a derepression of a gene promoter. Consequently this protein is quite interesting for biotechnological applications. Indeed, knowing the different pathways and protein interactions leading to DNA damage repair is a meaningful goal in research especially in new cancer therapies. <br />
<br />
<br />
=== Catabolism of poly (ADP-ribose) ===<br />
<br />
This protein has four principal domains on a <scene name='82/829351/Single_chain/1'>single peptide chain</scene>: an A-domain, a catalytic domain and two substrate binding domains[http://www.uniprot.org/uniprot/Q86W56]. <br />
The first 456 amino acids of the peptide chain form the <scene name='82/829351/A_domain/1'>A-domain</scene>. Then, from the 610th to the 795th amino acids the <scene name='82/829351/Catalytic_domain/1'>catalytic domain</scene> can be found. This catalytic domain can bind to other proteins with <scene name='82/829351/Substrat_-_catalytic_domain/1'>two amino acids</scene> (the 726th and 727th amino acids). Next, <scene name='82/829351/Subtrat_jonction_domain_2/1'>the second substrate binding domain</scene> is located from the 869th to the 874th amino acid. [http://www.uniprot.org/uniprot/Q86W56]<br />
As such, most of the amino acids form the A-domain and the catalytic domain and only a few amino acids (8 a.a) make links with other proteins. Moreover, the ligand 7JB can bind the protein on the <scene name='82/829351/Liason_7jb/1'>754, 758, 792 and 795 amino acids</scene>. These amino acids are located on a helix and on a beta sheet. [http://www.rcsb.org/pdb/explore/remediatedSequence.do?structureId=6HMM]. There is the <scene name='82/829351/Distritbution_domain/1'>following</scene> amino acid distribution.<br />
<br />
The protein <scene name='82/829351/Parg/1'>PARG</scene> folds into an ADP-ribose-binding macro domain with an N-terminal extension. It also consists of a diphosphate-binding loop on one side of an ADP-ribose binding cavity. On the other side there are several amino acids matching to the specific <scene name='82/829351/Parg/1'>PARG</scene> signature sequence. <br />
In the macro domain fold, a loop is inserted to welcome the Glu115 side chain protecting the active site of the <scene name='82/829351/Parg/1'>PARG</scene> protein. This loop gives <scene name='82/829351/Parg/1'>PARG</scene> the ability to hydrolyze PAR. The <scene name='82/829351/Parg_active_site/1'>hydrolysis of PAR happens in PARG catalytic domain</scene>. (PAR is represented here in pink).<br />
<br />
<br />
<br />
=== Post-translational modifications ===<br />
<br />
The protein is a complex composed of the [[ poly (ADP-ribose) glycohydrolase]] (PARG) and the anthraquinone PDD00013907. The Poly(ADP-ribose)glycohydrolase can interact with either [[PCNA]] or [[NUDT5]], this gives various possible functions to the protein. When this protein binds with NUDT5 it can remodel chromatin for example [http://www.uniprot.org/uniprot/Q86W56]. The post-translational modifications of the PAR protein (poly ADP-ribose) are important for DNA stability. <br />
PDD00013907 is, as already stated, an anthraquinone which is a polycyclic aromatic hydrocarbon usually used in biopesticides as a pest repellant. Here it is considered as a free <scene name='82/829351/7jb/1'>ligand</scene> (of identification number on PDB: 7JB) that can bind to the <scene name='82/829351/Parg/1'>PARG</scene> creating the<scene name='82/829351/Complex/1'> protein complex 6HMM</scene>. <br />
<br />
There are several possible post-translational modifications to stabilize DNA. Most commonly there would be phosphorylation, acetylation or methylation <ref>PMID: 21037856</ref>.<br />
Another post-translational modification concerning the <scene name='82/829351/6hmm/2'>6HMM protein</scene> is made on the poly(ADP-ribose) protein (PAR). PAR is composed of a repetition of ADP-ribose units linked through glycosidic ribose-ribose bonds <ref>doi: 10.1038/nature10404</ref>. This allows the repair of single-strand breaks on DNA <ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792.">DOI: 10.1021/acs.jmedchem.8b01407</ref>. The Poly (ADP-ribose) polymerase (PARP), more specifically the subtype [http://www.uniprot.org/uniprot/P09874 PARP1], will recognize and will bind to the single-stranded break on the DNA. It will then autophosphorylate and form PAR chains. These will recruit other repair proteins to the site. The role of <scene name='82/829351/Parg/1'>PARG</scene> is the hydrolyzation of the specific ribose-ribose bonds present in PAR which leads to its degradation and as such the reparation cycle will be finished<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/>.<br />
<br />
The anthraquinone PDD00013907 is a weakly active and cytotoxic anthraquinone 8a acting as a free ligand binding in the ADP-ribose binding site of the <scene name='82/829351/Parg/1'>PARG</scene>. This PDD00013907 should lead to the inhibition of <scene name='82/829351/Parg/1'>PARG</scene>, which is of interest in the search of novel cancer therapies <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. <br />
<br />
<br />
<br />
=== Diseases and Treatment ===<br />
<br />
Due to the function of the protein poly (ADP-ribose) glycohydrolase <scene name='82/829351/Parg/1'>PARG</scene> to be part of post-translational processes of DNA damage repair it could be used for new treatments in cancer therapy or for ther diseases. In cancer cells the rate of DNA damage is most probably higher than in normal cells. This could result from the considerably raised stress levels. A deficiency of <scene name='82/829351/Parg/1'>PARG</scene> results in the cessing of the cell cycle and the following cell death<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/><ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. Consequently, the inhibition of <scene name='82/829351/Parg/1'>PARG</scene> might be a solution on how to destroy tumor cells, for example.<br />
<br />
The PAR protein is a potential target in drug discovery as there are no close homologues of <scene name='82/829351/Parg/1'>PARG</scene>. That’s why there has already been a lot of research concerning novel treatments.<br />
<br />
The goal of searched therapeutics is to find a way to get the protein <scene name='82/829351/Parg/1'>PARG</scene> into a complex that is acting similar to the <scene name='82/829351/Parg/1'>6HMM complex</scene>.Indeed the protein in complex with the anthraquinone does not work properly anymore [http://www.rcsb.org/structure/6HMM], the described complex shows how an inhibited <scene name='82/829351/Parg/1'>PARG</scene> might act in the cell. For now, the research for anthraquinone as inhibitor has stopped as it is cytotoxic for the cell<ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>.<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Laurine Grimandihttps://proteopedia.org/index.php?title=Sandbox_Reserved_1098&diff=3505772Sandbox Reserved 10982022-01-21T22:03:33Z<p>Laurine Grimandi: </p>
<hr />
<div>{{Sandbox_ESBS_2019}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==6HMM== <br />
<StructureSection load='6hmm' size='340' side='right' caption='[[6hmm]]' scene=''><br />
The <scene name='82/829351/6hmm/2'>6HMM protein</scene> is a human[[ poly (ADP-ribose) glycohydrolase]].It is the major enzyme responsible for the catabolism of poly (ADP-ribose), a reversible covalent-modifier of chromosomal proteins. The protein is found in many tissues and may be subject to proteolysis generating smaller, active products.<br />
This protein is only present when the DNA is damaged. It influences the damaged chromatin through a derepression of a gene promoter. Consequently this protein is quite interesting for biotechnological applications. Indeed, knowing the different pathways and protein interactions leading to DNA damage repair is a meaningful goal in research especially in new cancer therapies. <br />
<br />
<br />
=== Catabolism of poly (ADP-ribose) ===<br />
<br />
This protein has four principal domains on a <scene name='82/829351/Single_chain/1'>single peptide chain</scene>: an A-domain, a catalytic domain and two substrate binding domains[http://www.uniprot.org/uniprot/Q86W56]. <br />
The first 456 amino acids of the peptide chain form the <scene name='82/829351/A_domain/1'>A-domain</scene>. Then, from the 610th to the 795th amino acids the <scene name='82/829351/Catalytic_domain/1'>catalytic domain</scene> can be found. This catalytic domain can bind to other proteins with <scene name='82/829351/Substrat_-_catalytic_domain/1'>two amino acids</scene> (the 726th and 727th amino acids). Next, <scene name='82/829351/Subtrat_jonction_domain_2/1'>the second substrate binding domain</scene> is located from the 869th to the 874th amino acid. [http://www.uniprot.org/uniprot/Q86W56]<br />
As such, most of the amino acids form the A-domain and the catalytic domain and only a few amino acids (8 a.a) make links with other proteins. Moreover, the ligand 7JB can bind the protein on the <scene name='82/829351/Liason_7jb/1'>754, 758, 792 and 795 amino acids</scene>. These amino acids are located on a helix and on a beta sheet. [http://www.rcsb.org/pdb/explore/remediatedSequence.do?structureId=6HMM]. There is the <scene name='82/829351/Distritbution_domain/1'>following</scene> amino acid distribution.<br />
<br />
The protein <scene name='82/829351/Parg/1'>PARG</scene> folds into an ADP-ribose-binding macro domain with an N-terminal extension. It also consists of a diphosphate-binding loop on one side of an ADP-ribose binding cavity. On the other side there are several amino acids matching to the specific <scene name='82/829351/Parg/1'>PARG</scene> signature sequence. <br />
In the macro domain fold, a loop is inserted to welcome the Glu115 side chain protecting the active site of the <scene name='82/829351/Parg/1'>PARG</scene> protein. This loop gives <scene name='82/829351/Parg/1'>PARG</scene> the ability to hydrolyze PAR. The <scene name='82/829351/Parg_active_site/1'>hydrolysis of PAR happens in PARG catalytic domain</scene>. (PAR is represented here in pink).<br />
<br />
<br />
<br />
=== Post-translational modifications ===<br />
<br />
The protein is a complex composed of the [[ poly (ADP-ribose) glycohydrolase]] (PARG) and the anthraquinone PDD00013907. The Poly(ADP-ribose)glycohydrolase can interact with either [[PCNA]] or [[NUDT5]], this gives various possible functions to the protein. When this protein binds with NUDT5 it can remodel chromatin for example [http://www.uniprot.org/uniprot/Q86W56]. The post-translational modifications of the PAR protein (poly ADP-ribose) are important for DNA stability. <br />
PDD00013907 is, as already stated, an anthraquinone which is a polycyclic aromatic hydrocarbon usually used in biopesticides as a pest repellant. Here it is considered as a free <scene name='82/829351/7jb/1'>ligand</scene> (of identification number on PDB: 7JB) that can bind to the <scene name='82/829351/Parg/1'>PARG</scene> creating the<scene name='82/829351/Complex/1'> protein complex 6HMM</scene>. <br />
<br />
There are several possible post-translational modifications to stabilize DNA. Most commonly there would be phosphorylation, acetylation or methylation <ref>PMID: 21037856</ref>.<br />
Another post-translational modification concerning the <scene name='82/829351/6hmm/2'>6HMM protein</scene> is made on the poly(ADP-ribose) protein (PAR). PAR is composed of a repetition of ADP-ribose units linked through glycosidic ribose-ribose bonds <ref>doi: 10.1038/nature10404</ref>. This allows the repair of single-strand breaks on DNA <ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792.">DOI: 10.1021/acs.jmedchem.8b01407</ref>. The Poly (ADP-ribose) polymerase (PARP), more specifically the subtype [http://www.uniprot.org/uniprot/P09874 PARP1], will recognize and will bind to the single-stranded break on the DNA. It will then autophosphorylate and form PAR chains. These will recruit other repair proteins to the site. The role of PARG is the hydrolyzation of the specific ribose-ribose bonds present in PAR which leads to its degradation and as such the reparation cycle will be finished<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/>.<br />
<br />
The anthraquinone PDD00013907 is a weakly active and cytotoxic anthraquinone 8a acting as a free ligand binding in the ADP-ribose binding site of the <scene name='82/829351/Parg/1'>PARG</scene>. This PDD00013907 should lead to the inhibition of <scene name='82/829351/Parg/1'>PARG</scene>, which is of interest in the search of novel cancer therapies <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. <br />
<br />
<br />
<br />
=== Diseases and Treatment ===<br />
<br />
Due to the function of the protein poly (ADP-ribose) glycohydrolase <scene name='82/829351/Parg/1'>PARG</scene> to be part of post-translational processes of DNA damage repair it could be used for new treatments in cancer therapy or for ther diseases. In cancer cells the rate of DNA damage is most probably higher than in normal cells. This could result from the considerably raised stress levels. A deficiency of <scene name='82/829351/Parg/1'>PARG</scene> results in the cessing of the cell cycle and the following cell death<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/><ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. Consequently, the inhibition of <scene name='82/829351/Parg/1'>PARG</scene> might be a solution on how to destroy tumor cells, for example.<br />
<br />
The PAR protein is a potential target in drug discovery as there are no close homologues of <scene name='82/829351/Parg/1'>PARG</scene>. That’s why there has already been a lot of research concerning novel treatments.<br />
<br />
The goal of searched therapeutics is to find a way to get the protein <scene name='82/829351/Parg/1'>PARG</scene> into a complex that is acting similar to the <scene name='82/829351/Parg/1'>6HMM complex</scene>.Indeed the protein in complex with the anthraquinone does not work properly anymore [http://www.rcsb.org/structure/6HMM], the described complex shows how an inhibited <scene name='82/829351/Parg/1'>PARG</scene> might act in the cell. For now, the research for anthraquinone as inhibitor has stopped as it is cytotoxic for the cell<ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>.<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Laurine Grimandihttps://proteopedia.org/index.php?title=Sandbox_Reserved_1098&diff=3505771Sandbox Reserved 10982022-01-21T22:00:23Z<p>Laurine Grimandi: </p>
<hr />
<div>{{Sandbox_ESBS_2019}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==6HMM== <br />
<StructureSection load='6hmm' size='340' side='right' caption='[[6hmm]]' scene=''><br />
The <scene name='82/829351/6hmm/2'>6HMM protein</scene> is a human[[ poly (ADP-ribose) glycohydrolase]].It is the major enzyme responsible for the catabolism of poly (ADP-ribose), a reversible covalent-modifier of chromosomal proteins. The protein is found in many tissues and may be subject to proteolysis generating smaller, active products.<br />
This protein is only present when the DNA is damaged. It influences the damaged chromatin through a derepression of a gene promoter. Consequently this protein is quite interesting for biotechnological applications. Indeed, knowing the different pathways and protein interactions leading to DNA damage repair is a meaningful goal in research especially in new cancer therapies. <br />
<br />
<br />
=== Catabolism of poly (ADP-ribose) ===<br />
<br />
This protein has four principal domains on a <scene name='82/829351/Single_chain/1'>single peptide chain</scene>: an A-domain, a catalytic domain and two substrate binding domains[http://www.uniprot.org/uniprot/Q86W56]. <br />
The first 456 amino acids of the peptide chain form the <scene name='82/829351/A_domain/1'>A-domain</scene>. Then, from the 610th to the 795th amino acids the <scene name='82/829351/Catalytic_domain/1'>catalytic domain</scene> can be found. This catalytic domain can bind to other proteins with <scene name='82/829351/Substrat_-_catalytic_domain/1'>two amino acids</scene> (the 726th and 727th amino acids). Next, <scene name='82/829351/Subtrat_jonction_domain_2/1'>the second substrate binding domain</scene> is located from the 869th to the 874th amino acid. [http://www.uniprot.org/uniprot/Q86W56]<br />
As such, most of the amino acids form the A-domain and the catalytic domain and only a few amino acids (8 a.a) make links with other proteins. Moreover, the ligand 7JB can bind the protein on the <scene name='82/829351/Liason_7jb/1'>754, 758, 792 and 795 amino acids</scene>. These amino acids are located on a helix and on a beta sheet. [http://www.rcsb.org/pdb/explore/remediatedSequence.do?structureId=6HMM]. There is the <scene name='82/829351/Distritbution_domain/1'>following</scene> amino acid distribution.<br />
<br />
The protein <scene name='82/829351/Parg/1'>PARG</scene> folds into an ADP-ribose-binding macro domain with an N-terminal extension. It also consists of a diphosphate-binding loop on one side of an ADP-ribose binding cavity. On the other side there are several amino acids matching to the specific <scene name='82/829351/Parg/1'>PARG</scene> signature sequence. <br />
In the macro domain fold, a loop is inserted to welcome the Glu115 side chain protecting the active site of the <scene name='82/829351/Parg/1'>PARG</scene> protein. This loop gives <scene name='82/829351/Parg/1'>PARG</scene> the ability to hydrolyze PAR. The <scene name='82/829351/Parg_active_site/1'>hydrolysis of PAR happens in PARG catalytic domain</scene>. (PAR is represented here in pink).<br />
<br />
<br />
<br />
=== Post-translational modifications ===<br />
<br />
The protein is a complex composed of the [[ poly (ADP-ribose) glycohydrolase]] (PARG) and the anthraquinone PDD00013907. The Poly(ADP-ribose)glycohydrolase can interact with either [[PCNA]] or [[NUDT5]], this gives various possible functions to the protein. When this protein binds with NUDT5 it can remodel chromatin for example [http://www.uniprot.org/uniprot/Q86W56]. The post-translational modifications of the PAR protein (poly ADP-ribose) are important for DNA stability. <br />
PDD00013907 is, as already stated, an anthraquinone which is a polycyclic aromatic hydrocarbon usually used in biopesticides as a pest repellant. Here it is considered as a free <scene name='82/829351/7jb/1'>ligand</scene> (of identification number on PDB: 7JB) that can bind to the <scene name='82/829351/Parg/1'>PARG</scene> creating the<scene name='82/829351/Complex/1'> protein complex 6HMM</scene>. <br />
<br />
There are several possible post-translational modifications to stabilize DNA. Most commonly there would be phosphorylation, acetylation or methylation <ref>PMID: 21037856</ref>.<br />
Another post-translational modification concerning the <scene name='82/829351/6hmm/2'>6HMM protein</scene> is made on the poly(ADP-ribose) protein (PAR). PAR is composed of a repetition of ADP-ribose units linked through glycosidic ribose-ribose bonds <ref>doi: 10.1038/nature10404</ref>. This allows the repair of single-strand breaks on DNA <ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792.">DOI: 10.1021/acs.jmedchem.8b01407</ref>. The Poly (ADP-ribose) polymerase (PARP), more specifically the subtype [http://www.uniprot.org/uniprot/P09874 PARP1], will recognize and will bind to the single-stranded break on the DNA. It will then autophosphorylate and form PAR chains. These will recruit other repair proteins to the site. The role of PARG is the hydrolyzation of the specific ribose-ribose bonds present in PAR which leads to its degradation and as such the reparation cycle will be finished<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/>.<br />
<br />
The anthraquinone PDD00013907 is a weakly active and cytotoxic anthraquinone 8a acting as a free ligand binding in the ADP-ribose binding site of the <scene name='82/829351/Parg/1'>PARG</scene>. This PDD00013907 should lead to the inhibition of <scene name='82/829351/Parg/1'>PARG</scene>, which is of interest in the search of novel cancer therapies <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. <br />
<br />
<br />
<br />
== Diseases and Treatment ==<br />
<br />
Due to the function of the protein poly (ADP-ribose) glycohydrolase <scene name='82/829351/Parg/1'>PARG</scene> to be part of post-translational processes of DNA damage repair it could be used for new treatments in cancer therapy or for ther diseases. In cancer cells the rate of DNA damage is most probably higher than in normal cells. This could result from the considerably raised stress levels. A deficiency of <scene name='82/829351/Parg/1'>PARG</scene> results in the cessing of the cell cycle and the following cell death<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/><ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. Consequently, the inhibition of <scene name='82/829351/Parg/1'>PARG</scene> might be a solution on how to destroy tumor cells, for example.<br />
<br />
The PAR protein is a potential target in drug discovery as there are no close homologues of <scene name='82/829351/Parg/1'>PARG</scene>. That’s why there has already been a lot of research concerning novel treatments.<br />
<br />
The goal of searched therapeutics is to find a way to get the protein <scene name='82/829351/Parg/1'>PARG</scene> into a complex that is acting similar to the <scene name='82/829351/Parg/1'>6HMM complex</scene>.Indeed the protein in complex with the anthraquinone does not work properly anymore [http://www.rcsb.org/structure/6HMM], the described complex shows how an inhibited <scene name='82/829351/Parg/1'>PARG</scene> might act in the cell. For now, the research for anthraquinone as inhibitor has stopped as it is cytotoxic for the cell<ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>.<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Laurine Grimandihttps://proteopedia.org/index.php?title=Sandbox_Reserved_1098&diff=3505770Sandbox Reserved 10982022-01-21T21:58:51Z<p>Laurine Grimandi: </p>
<hr />
<div>{{Sandbox_ESBS_2019}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==6HMM== <br />
<StructureSection load='6hmm' size='340' side='right' caption='[[6hmm]]' scene=''><br />
The <scene name='82/829351/6hmm/2'>6HMM protein</scene> is a human[[ poly (ADP-ribose) glycohydrolase]].It is the major enzyme responsible for the catabolism of poly (ADP-ribose), a reversible covalent-modifier of chromosomal proteins. The protein is found in many tissues and may be subject to proteolysis generating smaller, active products.<br />
This protein is only present when the DNA is damaged. It influences the damaged chromatin through a derepression of a gene promoter. Consequently this protein is quite interesting for biotechnological applications. Indeed, knowing the different pathways and protein interactions leading to DNA damage repair is a meaningful goal in research especially in new cancer therapies. <br />
<br />
<br />
=== Catabolism of poly (ADP-ribose) ===<br />
<br />
This protein has four principal domains on a <scene name='82/829351/Single_chain/1'>single peptide chain</scene>: an A-domain, a catalytic domain and two substrate binding domains[http://www.uniprot.org/uniprot/Q86W56]. <br />
The first 456 amino acids of the peptide chain form the <scene name='82/829351/A_domain/1'>A-domain</scene>. Then, from the 610th to the 795th amino acids the <scene name='82/829351/Catalytic_domain/1'>catalytic domain</scene> can be found. This catalytic domain can bind to other proteins with <scene name='82/829351/Substrat_-_catalytic_domain/1'>two amino acids</scene> (the 726th and 727th amino acids). Next, <scene name='82/829351/Subtrat_jonction_domain_2/1'>the second substrate binding domain</scene> is located from the 869th to the 874th amino acid. [http://www.uniprot.org/uniprot/Q86W56]<br />
As such, most of the amino acids form the A-domain and the catalytic domain and only a few amino acids (8 a.a) make links with other proteins. Moreover, the ligand 7JB can bind the protein on the <scene name='82/829351/Liason_7jb/1'>754, 758, 792 and 795 amino acids</scene>. These amino acids are located on a helix and on a beta sheet. [http://www.rcsb.org/pdb/explore/remediatedSequence.do?structureId=6HMM]. There is the <scene name='82/829351/Distritbution_domain/1'>following</scene> amino acid distribution.<br />
<br />
The protein <scene name='82/829351/Parg/1'>PARG</scene> folds into an ADP-ribose-binding macro domain with an N-terminal extension. It also consists of a diphosphate-binding loop on one side of an ADP-ribose binding cavity. On the other side there are several amino acids matching to the specific <scene name='82/829351/Parg/1'>PARG</scene> signature sequence. <br />
In the macro domain fold, a loop is inserted to welcome the Glu115 side chain protecting the active site of the <scene name='82/829351/Parg/1'>PARG</scene> protein. This loop gives <scene name='82/829351/Parg/1'>PARG</scene> the ability to hydrolyze PAR. The <scene name='82/829351/Parg_active_site/1'>hydrolysis of PAR happens in PARG catalytic domain</scene>. (PAR is represented here in pink).<br />
<br />
<br />
<br />
=== Post-translational modifications ===<br />
<br />
The protein is a complex composed of the [[ poly (ADP-ribose) glycohydrolase]] (PARG) and the anthraquinone PDD00013907. The Poly(ADP-ribose)glycohydrolase can interact with either [[PCNA]] or [[NUDT5]], this gives various possible functions to the protein. When this protein binds with NUDT5 it can remodel chromatin for example [http://www.uniprot.org/uniprot/Q86W56]. The post-translational modifications of the PAR protein (poly ADP-ribose) are important for DNA stability. <br />
PDD00013907 is, as already stated, an anthraquinone which is a polycyclic aromatic hydrocarbon usually used in biopesticides as a pest repellant. Here it is considered as a free <scene name='82/829351/7jb/1'>ligand</scene> (of identification number on PDB: 7JB) that can bind to the <scene name='82/829351/Parg/1'>PARG</scene> creating the<scene name='82/829351/Complex/1'> protein complex 6HMM</scene>. <br />
<br />
There are several possible post-translational modifications to stabilize DNA. Most commonly there would be phosphorylation, acetylation or methylation <ref>PMID: 21037856</ref>.<br />
Another post-translational modification concerning the 6HMM protein is made on the poly(ADP-ribose) protein (PAR). PAR is composed of a repetition of ADP-ribose units linked through glycosidic ribose-ribose bonds <ref>doi: 10.1038/nature10404</ref>. This allows the repair of single-strand breaks on DNA <ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792.">DOI: 10.1021/acs.jmedchem.8b01407</ref>. The Poly (ADP-ribose) polymerase (PARP), more specifically the subtype [http://www.uniprot.org/uniprot/P09874 PARP1], will recognize and will bind to the single-stranded break on the DNA. It will then autophosphorylate and form PAR chains. These will recruit other repair proteins to the site. The role of PARG is the hydrolyzation of the specific ribose-ribose bonds present in PAR which leads to its degradation and as such the reparation cycle will be finished<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/>.<br />
<br />
The anthraquinone PDD00013907 is a weakly active and cytotoxic anthraquinone 8a acting as a free ligand binding in the ADP-ribose binding site of the <scene name='82/829351/Parg/1'>PARG</scene>. This PDD00013907 should lead to the inhibition of <scene name='82/829351/Parg/1'>PARG</scene>, which is of interest in the search of novel cancer therapies <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. <br />
<br />
<br />
<br />
== Diseases and Treatment ==<br />
<br />
Due to the function of the protein poly (ADP-ribose) glycohydrolase <scene name='82/829351/Parg/1'>PARG</scene> to be part of post-translational processes of DNA damage repair it could be used for new treatments in cancer therapy or for ther diseases. In cancer cells the rate of DNA damage is most probably higher than in normal cells. This could result from the considerably raised stress levels. A deficiency of <scene name='82/829351/Parg/1'>PARG</scene> results in the cessing of the cell cycle and the following cell death<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/><ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. Consequently, the inhibition of <scene name='82/829351/Parg/1'>PARG</scene> might be a solution on how to destroy tumor cells, for example.<br />
<br />
The PAR protein is a potential target in drug discovery as there are no close homologues of <scene name='82/829351/Parg/1'>PARG</scene>. That’s why there has already been a lot of research concerning novel treatments.<br />
<br />
The goal of searched therapeutics is to find a way to get the protein <scene name='82/829351/Parg/1'>PARG</scene> into a complex that is acting similar to the <scene name='82/829351/Parg/1'>6HMM complex</scene>.Indeed the protein in complex with the anthraquinone does not work properly anymore [http://www.rcsb.org/structure/6HMM], the described complex shows how an inhibited <scene name='82/829351/Parg/1'>PARG</scene> might act in the cell. For now, the research for anthraquinone as inhibitor has stopped as it is cytotoxic for the cell<ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>.<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Laurine Grimandihttps://proteopedia.org/index.php?title=Sandbox_Reserved_1098&diff=3505769Sandbox Reserved 10982022-01-21T21:57:26Z<p>Laurine Grimandi: </p>
<hr />
<div>{{Sandbox_ESBS_2019}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==6HMM== <br />
<StructureSection load='6hmm' size='340' side='right' caption='[[6hmm]]' scene=''><br />
The <scene name='82/829351/6hmm/2'>6HMM protein</scene> is a human[[ poly (ADP-ribose) glycohydrolase]].It is the major enzyme responsible for the catabolism of poly (ADP-ribose), a reversible covalent-modifier of chromosomal proteins. The protein is found in many tissues and may be subject to proteolysis generating smaller, active products.<br />
This protein is only present when the DNA is damaged. It influences the damaged chromatin through a derepression of a gene promoter. Consequently this protein is quite interesting for biotechnological applications. Indeed, knowing the different pathways and protein interactions leading to DNA damage repair is a meaningful goal in research especially in new cancer therapies. <br />
<br />
<br />
=== Catabolism of poly (ADP-ribose) ===<br />
<br />
This protein has four principal domains on a <scene name='82/829351/Single_chain/1'>single peptide chain</scene>: an A-domain, a catalytic domain and two substrate binding domains[http://www.uniprot.org/uniprot/Q86W56]. <br />
The first 456 amino acids of the peptide chain form the <scene name='82/829351/A_domain/1'>A-domain</scene>. Then, from the 610th to the 795th amino acids the <scene name='82/829351/Catalytic_domain/1'>catalytic domain</scene> can be found. This catalytic domain can bind to other proteins with <scene name='82/829351/Substrat_-_catalytic_domain/1'>two amino acids</scene> (the 726th and 727th amino acids). Next, <scene name='82/829351/Subtrat_jonction_domain_2/1'>the second substrate binding domain</scene> is located from the 869th to the 874th amino acid. [http://www.uniprot.org/uniprot/Q86W56]<br />
As such, most of the amino acids form the A-domain and the catalytic domain and only a few amino acids (8 a.a) make links with other proteins. Moreover, the ligand 7JB can bind the protein on the <scene name='82/829351/Liason_7jb/1'>754, 758, 792 and 795 amino acids</scene>. These amino acids are located on a helix and on a beta sheet. [http://www.rcsb.org/pdb/explore/remediatedSequence.do?structureId=6HMM]. There is the <scene name='82/829351/Distritbution_domain/1'>following</scene> amino acid distribution.<br />
<br />
<br />
The protein <scene name='82/829351/Parg/1'>PARG</scene> folds into an ADP-ribose-binding macro domain with an N-terminal extension. It also consists of a diphosphate-binding loop on one side of an ADP-ribose binding cavity. On the other side there are several amino acids matching to the specific <scene name='82/829351/Parg/1'>PARG</scene> signature sequence. <br />
In the macro domain fold, a loop is inserted to welcome the Glu115 side chain protecting the active site of the <scene name='82/829351/Parg/1'>PARG</scene> protein. This loop gives <scene name='82/829351/Parg/1'>PARG</scene> the ability to hydrolyze PAR. The <scene name='82/829351/Parg_active_site/1'>hydrolysis of PAR happens in PARG catalytic domain</scene>. (PAR is represented here in pink).<br />
<br />
<br />
=== Post-translational modifications ===<br />
<br />
The protein is a complex composed of the [[ poly (ADP-ribose) glycohydrolase]] (PARG) and the anthraquinone PDD00013907. The Poly(ADP-ribose)glycohydrolase can interact with either [[PCNA]] or [[NUDT5]], this gives various possible functions to the protein. When this protein binds with NUDT5 it can remodel chromatin for example [http://www.uniprot.org/uniprot/Q86W56]. The post-translational modifications of the PAR protein (poly ADP-ribose) are important for DNA stability. <br />
PDD00013907 is, as already stated, an anthraquinone which is a polycyclic aromatic hydrocarbon usually used in biopesticides as a pest repellant. Here it is considered as a free <scene name='82/829351/7jb/1'>ligand</scene> (of identification number on PDB: 7JB) that can bind to the <scene name='82/829351/Parg/1'>PARG</scene> creating the<scene name='82/829351/Complex/1'> protein complex 6HMM</scene>. <br />
<br />
<br />
There are several possible post-translational modifications to stabilize DNA. Most commonly there would be phosphorylation, acetylation or methylation <ref>PMID: 21037856</ref>.<br />
Another post-translational modification concerning the 6HMM protein is made on the poly(ADP-ribose) protein (PAR). PAR is composed of a repetition of ADP-ribose units linked through glycosidic ribose-ribose bonds <ref>doi: 10.1038/nature10404</ref>. This allows the repair of single-strand breaks on DNA <ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792.">DOI: 10.1021/acs.jmedchem.8b01407</ref>. The Poly (ADP-ribose) polymerase (PARP), more specifically the subtype [http://www.uniprot.org/uniprot/P09874 PARP1], will recognize and will bind to the single-stranded break on the DNA. It will then autophosphorylate and form PAR chains. These will recruit other repair proteins to the site. The role of PARG is the hydrolyzation of the specific ribose-ribose bonds present in PAR which leads to its degradation and as such the reparation cycle will be finished<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/>.<br />
<br />
<br />
The anthraquinone PDD00013907 is a weakly active and cytotoxic anthraquinone 8a acting as a free ligand binding in the ADP-ribose binding site of the <scene name='82/829351/Parg/1'>PARG</scene>. This PDD00013907 should lead to the inhibition of <scene name='82/829351/Parg/1'>PARG</scene>, which is of interest in the search of novel cancer therapies <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. <br />
<br />
<br />
<br />
== Diseases and Treatment ==<br />
Due to the function of the protein poly (ADP-ribose) glycohydrolase <scene name='82/829351/Parg/1'>PARG</scene> to be part of post-translational processes of DNA damage repair it could be used for new treatments in cancer therapy or for ther diseases. In cancer cells the rate of DNA damage is most probably higher than in normal cells. This could result from the considerably raised stress levels. A deficiency of <scene name='82/829351/Parg/1'>PARG</scene> results in the cessing of the cell cycle and the following cell death<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/><ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. Consequently, the inhibition of <scene name='82/829351/Parg/1'>PARG</scene> might be a solution on how to destroy tumor cells, for example.<br />
<br />
The PAR protein is a potential target in drug discovery as there are no close homologues of <scene name='82/829351/Parg/1'>PARG</scene>. That’s why there has already been a lot of research concerning novel treatments.<br />
<br />
The goal of searched therapeutics is to find a way to get the protein <scene name='82/829351/Parg/1'>PARG</scene> into a complex that is acting similar to the <scene name='82/829351/Parg/1'>6HMM complex</scene>.Indeed the protein in complex with the anthraquinone does not work properly anymore [http://www.rcsb.org/structure/6HMM], the described complex shows how an inhibited <scene name='82/829351/Parg/1'>PARG</scene> might act in the cell. For now, the research for anthraquinone as inhibitor has stopped as it is cytotoxic for the cell<ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>.<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Laurine Grimandihttps://proteopedia.org/index.php?title=Sandbox_Reserved_1098&diff=3505768Sandbox Reserved 10982022-01-21T21:55:27Z<p>Laurine Grimandi: </p>
<hr />
<div>{{Sandbox_ESBS_2019}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==6HMM== <br />
<StructureSection load='6hmm' size='340' side='right' caption='[[6hmm]]' scene=''><br />
The <scene name='82/829351/6hmm/2'>6HMM protein</scene> is a human[[ poly (ADP-ribose) glycohydrolase]].It is the major enzyme responsible for the catabolism of poly (ADP-ribose), a reversible covalent-modifier of chromosomal proteins. The protein is found in many tissues and may be subject to proteolysis generating smaller, active products.<br />
This protein is only present when the DNA is damaged. It influences the damaged chromatin through a derepression of a gene promoter. Consequently this protein is quite interesting for biotechnological applications. Indeed, knowing the different pathways and protein interactions leading to DNA damage repair is a meaningful goal in research especially in new cancer therapies. <br />
<br />
<br />
=== Catabolism of poly (ADP-ribose) ===<br />
<br />
This protein has four principal domains on a <scene name='82/829351/Single_chain/1'>single peptide chain</scene>: an A-domain, a catalytic domain and two substrate binding domains[http://www.uniprot.org/uniprot/Q86W56]. <br />
The first 456 amino acids of the peptide chain form the <scene name='82/829351/A_domain/1'>A-domain</scene>. Then, from the 610th to the 795th amino acids the <scene name='82/829351/Catalytic_domain/1'>catalytic domain</scene> can be found. This catalytic domain can bind to other proteins with <scene name='82/829351/Substrat_-_catalytic_domain/1'>two amino acids</scene> (the 726th and 727th amino acids). Next, <scene name='82/829351/Subtrat_jonction_domain_2/1'>the second substrate binding domain</scene> is located from the 869th to the 874th amino acid. [http://www.uniprot.org/uniprot/Q86W56]<br />
As such, most of the amino acids form the A-domain and the catalytic domain and only a few amino acids (8 a.a) make links with other proteins. Moreover, the ligand 7JB can bind the protein on the <scene name='82/829351/Liason_7jb/1'>754, 758, 792 and 795 amino acids</scene>. These amino acids are located on a helix and on a beta sheet. [http://www.rcsb.org/pdb/explore/remediatedSequence.do?structureId=6HMM]. There is the <scene name='82/829351/Distritbution_domain/1'>following</scene> amino acid distribution.<br />
<br />
<br />
The protein <scene name='82/829351/Parg/1'>PARG</scene> folds into an ADP-ribose-binding macro domain with an N-terminal extension. It also consists of a diphosphate-binding loop on one side of an ADP-ribose binding cavity. On the other side there are several amino acids matching to the specific <scene name='82/829351/Parg/1'>PARG</scene> signature sequence. <br />
In the macro domain fold, a loop is inserted to welcome the Glu115 side chain protecting the active site of the <scene name='82/829351/Parg/1'>PARG</scene> protein. This loop gives <scene name='82/829351/Parg/1'>PARG</scene> the ability to hydrolyze PAR. The <scene name='82/829351/Parg_active_site/1'>hydrolysis of PAR happens in PARG catalytic domain</scene>. (PAR is represented here in pink).<br />
<br />
<br />
=== Post-translational modifications ===<br />
<br />
The protein is a complex composed of the [[ poly (ADP-ribose) glycohydrolase]] (PARG) and the anthraquinone PDD00013907. The Poly(ADP-ribose)glycohydrolase can interact with either [[PCNA]] or [[NUDT5]], this gives various possible functions to the protein. When this protein binds with NUDT5 it can remodel chromatin for example [http://www.uniprot.org/uniprot/Q86W56]. The post-translational modifications of the PAR protein (poly ADP-ribose) are important for DNA stability. <br />
PDD00013907 is, as already stated, an anthraquinone which is a polycyclic aromatic hydrocarbon usually used in biopesticides as a pest repellant. Here it is considered as a free <scene name='82/829351/7jb/1'>ligand</scene> (of identification number on PDB: 7JB) that can bind to the <scene name='82/829351/Parg/1'>PARG</scene> creating the<scene name='82/829351/Complex/1'> protein complex 6HMM</scene>. <br />
<br />
There are several possible post-translational modifications to stabilize DNA. Most commonly there would be phosphorylation, acetylation or methylation <ref>PMID: 21037856</ref>.<br />
Another post-translational modification concerning the 6HMM protein is made on the poly(ADP-ribose) protein (PAR). PAR is composed of a repetition of ADP-ribose units linked through glycosidic ribose-ribose bonds <ref>doi: 10.1038/nature10404</ref>. This allows the repair of single-strand breaks on DNA <ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792.">DOI: 10.1021/acs.jmedchem.8b01407</ref>. <br />
<br />
The Poly (ADP-ribose) polymerase (PARP), more specifically the subtype [http://www.uniprot.org/uniprot/P09874 PARP1], will recognize and will bind to the single-stranded break on the DNA. It will then autophosphorylate and form PAR chains. These will recruit other repair proteins to the site. The role of PARG is the hydrolyzation of the specific ribose-ribose bonds present in PAR which leads to its degradation and as such the reparation cycle will be finished<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/>.<br />
<br />
The anthraquinone PDD00013907 is a weakly active and cytotoxic anthraquinone 8a acting as a free ligand binding in the ADP-ribose binding site of the <scene name='82/829351/Parg/1'>PARG</scene>. This PDD00013907 should lead to the inhibition of <scene name='82/829351/Parg/1'>PARG</scene>, which is of interest in the search of novel cancer therapies <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. <br />
<br />
<br />
<br />
== Diseases and Treatment ==<br />
Due to the function of the protein poly (ADP-ribose) glycohydrolase <scene name='82/829351/Parg/1'>PARG</scene> to be part of post-translational processes of DNA damage repair it could be used for new treatments in cancer therapy or for ther diseases. In cancer cells the rate of DNA damage is most probably higher than in normal cells. This could result from the considerably raised stress levels. A deficiency of <scene name='82/829351/Parg/1'>PARG</scene> results in the cessing of the cell cycle and the following cell death<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/><ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. Consequently, the inhibition of <scene name='82/829351/Parg/1'>PARG</scene> might be a solution on how to destroy tumor cells, for example.<br />
<br />
The PAR protein is a potential target in drug discovery as there are no close homologues of <scene name='82/829351/Parg/1'>PARG</scene>. That’s why there has already been a lot of research concerning novel treatments.<br />
<br />
The goal of searched therapeutics is to find a way to get the protein <scene name='82/829351/Parg/1'>PARG</scene> into a complex that is acting similar to the <scene name='82/829351/Parg/1'>6HMM complex</scene>.Indeed the protein in complex with the anthraquinone does not work properly anymore [http://www.rcsb.org/structure/6HMM], the described complex shows how an inhibited <scene name='82/829351/Parg/1'>PARG</scene> might act in the cell. For now, the research for anthraquinone as inhibitor has stopped as it is cytotoxic for the cell<ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>.<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Laurine Grimandihttps://proteopedia.org/index.php?title=Sandbox_Reserved_1098&diff=3505767Sandbox Reserved 10982022-01-21T21:53:19Z<p>Laurine Grimandi: </p>
<hr />
<div>{{Sandbox_ESBS_2019}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==6HMM== <br />
<StructureSection load='6hmm' size='340' side='right' caption='[[6hmm]]' scene=''><br />
The <scene name='82/829351/6hmm/2'>6HMM protein</scene> is a human[[ poly (ADP-ribose) glycohydrolase]].It is the major enzyme responsible for the catabolism of poly (ADP-ribose), a reversible covalent-modifier of chromosomal proteins. The protein is found in many tissues and may be subject to proteolysis generating smaller, active products.<br />
This protein is only present when the DNA is damaged. It influences the damaged chromatin through a derepression of a gene promoter. Consequently this protein is quite interesting for biotechnological applications. Indeed, knowing the different pathways and protein interactions leading to DNA damage repair is a meaningful goal in research especially in new cancer therapies. <br />
<br />
<br />
=== Catabolism of poly (ADP-ribose) ===<br />
<br />
This protein has four principal domains on a <scene name='82/829351/Single_chain/1'>single peptide chain</scene>: an A-domain, a catalytic domain and two substrate binding domains[http://www.uniprot.org/uniprot/Q86W56]. <br />
The first 456 amino acids of the peptide chain form the <scene name='82/829351/A_domain/1'>A-domain</scene>. Then, from the 610th to the 795th amino acids the <scene name='82/829351/Catalytic_domain/1'>catalytic domain</scene> can be found. This catalytic domain can bind to other proteins with <scene name='82/829351/Substrat_-_catalytic_domain/1'>two amino acids</scene> (the 726th and 727th amino acids). Next, <scene name='82/829351/Subtrat_jonction_domain_2/1'>the second substrate binding domain</scene> is located from the 869th to the 874th amino acid. [http://www.uniprot.org/uniprot/Q86W56]<br />
As such, most of the amino acids form the A-domain and the catalytic domain and only a few amino acids (8 a.a) make links with other proteins. Moreover, the ligand 7JB can bind the protein on the <scene name='82/829351/Liason_7jb/1'>754, 758, 792 and 795 amino acids</scene>. These amino acids are located on a helix and on a beta sheet. [http://www.rcsb.org/pdb/explore/remediatedSequence.do?structureId=6HMM]. There is the <scene name='82/829351/Distritbution_domain/1'>following</scene> amino acid distribution.<br />
<br />
<br />
The protein <scene name='82/829351/Parg/1'>PARG</scene> folds into an ADP-ribose-binding macro domain with an N-terminal extension. It also consists of a diphosphate-binding loop on one side of an ADP-ribose binding cavity. On the other side there are several amino acids matching to the specific <scene name='82/829351/Parg/1'>PARG</scene> signature sequence. <br />
In the macro domain fold, a loop is inserted to welcome the Glu115 side chain protecting the active site of the <scene name='82/829351/Parg/1'>PARG</scene> protein. This loop gives <scene name='82/829351/Parg/1'>PARG</scene> the ability to hydrolyze PAR. The <scene name='82/829351/Parg_active_site/1'>hydrolysis of PAR happens in PARG catalytic domain</scene>. (PAR is represented here in pink).<br />
<br />
=== Post-translational modifications ===<br />
<br />
The protein is a complex composed of the [[ poly (ADP-ribose) glycohydrolase]] (PARG) and the anthraquinone PDD00013907. The Poly(ADP-ribose)glycohydrolase can interact with either [[PCNA]] or [[NUDT5]], this gives various possible functions to the protein. When this protein binds with NUDT5 it can remodel chromatin for example [http://www.uniprot.org/uniprot/Q86W56]. The post-translational modifications of the PAR protein (poly ADP-ribose) are important for DNA stability. <br />
PDD00013907 is, as already stated, an anthraquinone which is a polycyclic aromatic hydrocarbon usually used in biopesticides as a pest repellant. Here it is considered as a free <scene name='82/829351/7jb/1'>ligand</scene> (of identification number on PDB: 7JB) that can bind to the <scene name='82/829351/Parg/1'>PARG</scene> creating the<scene name='82/829351/Complex/1'> protein complex 6HMM</scene>. <br />
<br />
There are several possible post-translational modifications to stabilize DNA. Most commonly there would be phosphorylation, acetylation or methylation <ref>PMID: 21037856</ref>.<br />
<br />
Another post-translational modification concerning the 6HMM protein is made on the poly(ADP-ribose) protein (PAR). PAR is composed of a repetition of ADP-ribose units linked through glycosidic ribose-ribose bonds <ref>doi: 10.1038/nature10404</ref>. This allows the repair of single-strand breaks on DNA <ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792.">DOI: 10.1021/acs.jmedchem.8b01407</ref>. <br />
<br />
<br />
<scene name='82/829351/Parg/1'>PARG</scene>, a constituent of the <scene name='82/829351/6hmm/1'>6HMM protein</scene> <br />
will degrade PAR to allow the <scene name='82/829351/Parp1_on_dna/1'>poly (ADP-ribose) polymerase (PARP)</scene> to free itself from the damaged site, that is now repaired, and completes as such reparation <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12.">PMID: 27689388</ref>.<br />
<br />
<br />
The anthraquinone PDD00013907 is a weakly active and cytotoxic anthraquinone 8a acting as a free ligand binding in the ADP-ribose binding site of the <scene name='82/829351/Parg/1'>PARG</scene>. This PDD00013907 should lead to the inhibition of <scene name='82/829351/Parg/1'>PARG</scene>, which is of interest in the search of novel cancer therapies <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. <br />
<br />
=== The mechanism ===<br />
The Poly (ADP-ribose) polymerase (PARP), more specifically the subtype [http://www.uniprot.org/uniprot/P09874 PARP1], will recognize and will bind to the single-stranded break on the DNA. It will then autophosphorylate and form PAR chains. These will recruit other repair proteins to the site. <br />
<br />
The role of PARG is the hydrolyzation of the specific ribose-ribose bonds present in PAR which leads to its degradation and as such the reparation cycle will be finished<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/><br />
<br />
== Diseases and Treatment ==<br />
Due to the function of the protein poly (ADP-ribose) glycohydrolase <scene name='82/829351/Parg/1'>PARG</scene> to be part of post-translational processes of DNA damage repair it could be used for new treatments in cancer therapy or for ther diseases. In cancer cells the rate of DNA damage is most probably higher than in normal cells. This could result from the considerably raised stress levels. A deficiency of <scene name='82/829351/Parg/1'>PARG</scene> results in the cessing of the cell cycle and the following cell death<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/><ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. Consequently, the inhibition of <scene name='82/829351/Parg/1'>PARG</scene> might be a solution on how to destroy tumor cells, for example.<br />
<br />
The PAR protein is a potential target in drug discovery as there are no close homologues of <scene name='82/829351/Parg/1'>PARG</scene>. That’s why there has already been a lot of research concerning novel treatments.<br />
<br />
The goal of searched therapeutics is to find a way to get the protein <scene name='82/829351/Parg/1'>PARG</scene> into a complex that is acting similar to the <scene name='82/829351/Parg/1'>6HMM complex</scene>.Indeed the protein in complex with the anthraquinone does not work properly anymore [http://www.rcsb.org/structure/6HMM], the described complex shows how an inhibited <scene name='82/829351/Parg/1'>PARG</scene> might act in the cell. For now, the research for anthraquinone as inhibitor has stopped as it is cytotoxic for the cell<ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>.<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Laurine Grimandihttps://proteopedia.org/index.php?title=Sandbox_Reserved_1098&diff=3505766Sandbox Reserved 10982022-01-21T21:43:14Z<p>Laurine Grimandi: </p>
<hr />
<div>{{Sandbox_ESBS_2019}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==6HMM== <br />
<StructureSection load='6hmm' size='340' side='right' caption='[[6hmm]]' scene=''><br />
The <scene name='82/829351/6hmm/2'>6HMM protein</scene> is a human[[ poly (ADP-ribose) glycohydrolase]].It is the major enzyme responsible for the catabolism of poly (ADP-ribose), a reversible covalent-modifier of chromosomal proteins. The protein is found in many tissues and may be subject to proteolysis generating smaller, active products.<br />
This protein is only present when the DNA is damaged. It influences the damaged chromatin through a derepression of a gene promoter. Consequently this protein is quite interesting for biotechnological applications. Indeed, knowing the different pathways and protein interactions leading to DNA damage repair is a meaningful goal in research especially in new cancer therapies. <br />
<br />
<br />
=== Catabolism of poly (ADP-ribose) ===<br />
<br />
This protein has four principal domains on a <scene name='82/829351/Single_chain/1'>single peptide chain</scene>: an A-domain, a catalytic domain and two substrate binding domains[http://www.uniprot.org/uniprot/Q86W56]. <br />
The first 456 amino acids of the peptide chain form the <scene name='82/829351/A_domain/1'>A-domain</scene>. Then, from the 610th to the 795th amino acids the <scene name='82/829351/Catalytic_domain/1'>catalytic domain</scene> can be found. This catalytic domain can bind to other proteins with <scene name='82/829351/Substrat_-_catalytic_domain/1'>two amino acids</scene> (the 726th and 727th amino acids). Next, <scene name='82/829351/Subtrat_jonction_domain_2/1'>the second substrate binding domain</scene> is located from the 869th to the 874th amino acid. [http://www.uniprot.org/uniprot/Q86W56]<br />
As such, most of the amino acids form the A-domain and the catalytic domain and only a few amino acids (8 a.a) make links with other proteins. Moreover, the ligand 7JB can bind the protein on the <scene name='82/829351/Liason_7jb/1'>754, 758, 792 and 795 amino acids</scene>. These amino acids are located on a helix and on a beta sheet. [http://www.rcsb.org/pdb/explore/remediatedSequence.do?structureId=6HMM]. There is the <scene name='82/829351/Distritbution_domain/1'>following</scene> amino acid distribution.<br />
<br />
<br />
The protein <scene name='82/829351/Parg/1'>PARG</scene> folds into an ADP-ribose-binding macro domain with an N-terminal extension. It also consists of a diphosphate-binding loop on one side of an ADP-ribose binding cavity. On the other side there are several amino acids matching to the specific <scene name='82/829351/Parg/1'>PARG</scene> signature sequence. <br />
In the macro domain fold, a loop is inserted to welcome the Glu115 side chain protecting the active site of the <scene name='82/829351/Parg/1'>PARG</scene> protein. This loop gives <scene name='82/829351/Parg/1'>PARG</scene> the ability to hydrolyze PAR. The <scene name='82/829351/Parg_active_site/1'>hydrolysis of PAR happens in PARG catalytic domain</scene>. (PAR is represented here in pink).<br />
<br />
=== Post-translational modifications ===<br />
<br />
The protein is a complex composed of the [[ poly (ADP-ribose) glycohydrolase]] (PARG) and the anthraquinone PDD00013907. The Poly(ADP-ribose)glycohydrolase can interact with either [[PCNA]] or [[NUDT5]], this gives various possible functions to the protein. When this protein binds with NUDT5 it can remodel chromatin for example [http://www.uniprot.org/uniprot/Q86W56]. The post-translational modifications of the PAR protein (poly ADP-ribose) are important for DNA stability. <br />
PDD00013907 is, as already stated, an anthraquinone which is a polycyclic aromatic hydrocarbon usually used in biopesticides as a pest repellant. Here it is considered as a free <scene name='82/829351/7jb/1'>ligand</scene> (of identification number on PDB: 7JB) that can bind to the <scene name='82/829351/Parg/1'>PARG</scene> creating the<scene name='82/829351/Complex/1'> protein complex 6HMM</scene>. <br />
<br />
There are several possible post-translational modifications to stabilize DNA. Most commonly there would be phosphorylation, acetylation or methylation <ref>PMID: 21037856</ref>.<br />
<br />
Another post-translational modification concerning the 6HMM protein is made on the poly(ADP-ribose) protein (PAR). PAR is composed of a repetition of ADP-ribose units linked through glycosidic ribose-ribose bonds <ref>doi: 10.1038/nature10404</ref>. This allows the repair of single-strand breaks on DNA <ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792.">DOI: 10.1021/acs.jmedchem.8b01407</ref>. <scene name='82/829351/Parg/1'>PARG</scene>, a constituent of the <scene name='82/829351/6hmm/1'>6HMM protein</scene> will degrade PAR to allow the <scene name='82/829351/Parp1_on_dna/1'>poly (ADP-ribose) polymerase (PARP)</scene> to free itself from the damaged site, that is now repaired, and completes as such reparation <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12.">PMID: 27689388</ref>.<br />
<br />
The anthraquinone PDD00013907 is a weakly active and cytotoxic anthraquinone 8a acting as a free ligand binding in the ADP-ribose binding site of the <scene name='82/829351/Parg/1'>PARG</scene>. This PDD00013907 should lead to the inhibition of <scene name='82/829351/Parg/1'>PARG</scene>, which is of interest in the search of novel cancer therapies <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. <br />
<br />
=== The mechanism ===<br />
At first, the Poly (ADP-ribose) polymerase (PARP), more specifically the subtype [http://www.uniprot.org/uniprot/P09874 PARP1], will recognize and will bind to the single-stranded break on the DNA. It will then autophosphorylate due to NAD+ and form PAR chains. These will recruit other repair proteins to the site. <br />
<br />
The role of PARG is the hydrolyzation of the specific ribose-ribose bonds present in PAR which leads to its degradation and as such the reparation cycle will be finished<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/>. This degradation is important because without PARG the repair cycle cannot be completed <ref>PMID: 17548475</ref> and may lead to cell death. This is partially due to the still present PARP on the previously damaged site maintained by the non-degraded PAR <ref>PMID: 16140981</ref>. <br />
<br />
== Diseases and Treatment ==<br />
Due to the function of the protein poly (ADP-ribose) glycohydrolase <scene name='82/829351/Parg/1'>PARG</scene> to be part of post-translational processes of DNA damage repair it could be used for new treatments in cancer therapy or for ther diseases. In cancer cells the rate of DNA damage is most probably higher than in normal cells. This could result from the considerably raised stress levels. A deficiency of <scene name='82/829351/Parg/1'>PARG</scene> results in the cessing of the cell cycle and the following cell death<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/><ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. Consequently, the inhibition of <scene name='82/829351/Parg/1'>PARG</scene> might be a solution on how to destroy tumor cells, for example.<br />
<br />
The PAR protein is a potential target in drug discovery as there are no close homologues of <scene name='82/829351/Parg/1'>PARG</scene>. That’s why there has already been a lot of research concerning novel treatments.<br />
<br />
The goal of searched therapeutics is to find a way to get the protein <scene name='82/829351/Parg/1'>PARG</scene> into a complex that is acting similar to the <scene name='82/829351/Parg/1'>6HMM complex</scene>.Indeed the protein in complex with the anthraquinone does not work properly anymore [http://www.rcsb.org/structure/6HMM], the described complex shows how an inhibited <scene name='82/829351/Parg/1'>PARG</scene> might act in the cell. For now, the research for anthraquinone as inhibitor has stopped as it is cytotoxic for the cell<ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>.<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Laurine Grimandihttps://proteopedia.org/index.php?title=Sandbox_Reserved_1098&diff=3505764Sandbox Reserved 10982022-01-21T19:42:59Z<p>Laurine Grimandi: </p>
<hr />
<div>{{Sandbox_ESBS_2019}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==6HMM== <br />
<StructureSection load='6hmm' size='340' side='right' caption='[[6hmm]]' scene=''><br />
The <scene name='82/829351/6hmm/2'>6HMM protein</scene> is a human[[ poly (ADP-ribose) glycohydrolase]].It is the major enzyme responsible for the catabolism of poly (ADP-ribose), a reversible covalent-modifier of chromosomal proteins. The protein is found in many tissues and may be subject to proteolysis generating smaller, active products.<br />
This protein is only present when the DNA is damaged. It influences the damaged chromatin through a derepression of a gene promoter. Consequently this protein is quite interesting for biotechnological applications. Indeed, knowing the different pathways and protein interactions leading to DNA damage repair is a meaningful goal in research especially in new cancer therapies. <br />
<br />
<br />
=== Catabolism of poly (ADP-ribose) ===<br />
<br />
This protein has four principal domains on a <scene name='82/829351/Single_chain/1'>single peptide chain</scene>: an A-domain, a catalytic domain and two substrate binding domains[http://www.uniprot.org/uniprot/Q86W56]. <br />
The first 456 amino acids of the peptide chain form the <scene name='82/829351/A_domain/1'>A-domain</scene>. Then, from the 610th to the 795th amino acids the <scene name='82/829351/Catalytic_domain/1'>catalytic domain</scene> can be found. This catalytic domain can bind to other proteins with <scene name='82/829351/Substrat_-_catalytic_domain/1'>two amino acids</scene> (the 726th and 727th amino acids). Next, <scene name='82/829351/Subtrat_jonction_domain_2/1'>the second substrate binding domain</scene> is located from the 869th to the 874th amino acid. [http://www.uniprot.org/uniprot/Q86W56]<br />
As such, most of the amino acids form the A-domain and the catalytic domain and only a few amino acids (8 a.a) make links with other proteins. Moreover, the ligand 7JB can bind the protein on the <scene name='82/829351/Liason_7jb/1'>754, 758, 792 and 795 amino acids</scene>. These amino acids are located on a helix and on a beta sheet. [http://www.rcsb.org/pdb/explore/remediatedSequence.do?structureId=6HMM]. There is the <scene name='82/829351/Distritbution_domain/1'>following</scene> amino acid distribution.<br />
<br />
<br />
The protein <scene name='82/829351/Parg/1'>PARG</scene> folds into an ADP-ribose-binding macro domain with an N-terminal extension. It also consists of a diphosphate-binding loop on one side of an ADP-ribose binding cavity. On the other side there are several amino acids matching to the specific <scene name='82/829351/Parg/1'>PARG</scene> signature sequence. <br />
In the macro domain fold, a loop is inserted to welcome the Glu115 side chain protecting the active site of the <scene name='82/829351/Parg/1'>PARG</scene> protein. This loop gives <scene name='82/829351/Parg/1'>PARG</scene> the ability to hydrolyze PAR. The <scene name='82/829351/Parg_active_site/1'>hydrolysis of PAR happens in PARG catalytic domain</scene>. (PAR is represented here in pink).<br />
<br />
=== Post-translational modifications ===<br />
<br />
The protein is a complex composed of the [[ poly (ADP-ribose) glycohydrolase]] (PARG) and the anthraquinone PDD00013907. The Poly(ADP-ribose)glycohydrolase can interact with either [[PCNA]] or [[NUDT5]], this gives various possible functions to the protein. When this protein binds with NUDT5 it can remodel chromatin for example [http://www.uniprot.org/uniprot/Q86W56]. The post-translational modifications of the PAR protein (poly ADP-ribose) are important for DNA stability. <br />
PDD00013907 is, as already stated, an anthraquinone which is a polycyclic aromatic hydrocarbon usually used in biopesticides as a pest repellant. Here it is considered as a free <scene name='82/829351/7jb/1'>ligand</scene> (of identification number on PDB: 7JB) that can bind to the <scene name='82/829351/Parg/1'>PARG</scene> creating the<scene name='82/829351/Complex/1'> protein complex 6HMM</scene>. <br />
<br />
There are several possible post-translational modifications to stabilize DNA. Most commonly there would be phosphorylation, acetylation or methylation <ref>PMID: 21037856</ref>. Another post-translational modification concerning the 6HMM protein is made on the poly(ADP-ribose) protein (PAR). PAR is composed of a repetition of ADP-ribose units linked through glycosidic ribose-ribose bonds <ref>doi: 10.1038/nature10404</ref>. This allows the repair of single-strand breaks on DNA <ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792.">DOI: 10.1021/acs.jmedchem.8b01407</ref>. <scene name='82/829351/Parg/1'>PARG</scene>, a constituent of the <scene name='82/829351/6hmm/1'>6HMM protein</scene> will degrade PAR to allow the <scene name='82/829351/Parp1_on_dna/1'>poly (ADP-ribose) polymerase (PARP)</scene> to free itself from the damaged site, that is now repaired, and completes as such reparation <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12.">PMID: 27689388</ref>.<br />
<br />
The anthraquinone PDD00013907 is a weakly active and cytotoxic anthraquinone 8a acting as a free ligand binding in the ADP-ribose binding site of the <scene name='82/829351/Parg/1'>PARG</scene>. This PDD00013907 should lead to the inhibition of <scene name='82/829351/Parg/1'>PARG</scene>, which is of interest in the search of novel cancer therapies <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. <br />
<br />
=== The mechanism ===<br />
As said previously, poly(ADP-ribosylation) is an important post-translational modification for DNA repair. The mechanism behind this repair relies on several factors. At first, the Poly (ADP-ribose) polymerase (PARP), more specifically the subtype [http://www.uniprot.org/uniprot/P09874 PARP1], will recognize and will bind to the single-stranded break on the DNA. It will then autophosphorylate due to NAD+ and form PAR chains. These will recruit other repair proteins to the site. <br />
<br />
The role of PARG is the hydrolyzation of the specific ribose-ribose bonds present in PAR which leads to its degradation and as such the reparation cycle will be finished<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/>. This degradation is important because without PARG the repair cycle cannot be completed <ref>PMID: 17548475</ref> and may lead to cell death. This is partially due to the still present PARP on the previously damaged site maintained by the non-degraded PAR <ref>PMID: 16140981</ref>. <br />
<br />
== Diseases and Treatment ==<br />
Due to the function of the protein poly (ADP-ribose) glycohydrolase <scene name='82/829351/Parg/1'>PARG</scene> to be part of post-translational processes of DNA damage repair it could be used for new treatments in cancer therapy or for ther diseases. In cancer cells the rate of DNA damage is most probably higher than in normal cells. This could result from the considerably raised stress levels. A deficiency of <scene name='82/829351/Parg/1'>PARG</scene> results in the cessing of the cell cycle and the following cell death<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/><ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. Consequently, the inhibition of <scene name='82/829351/Parg/1'>PARG</scene> might be a solution on how to destroy tumor cells, for example.<br />
<br />
The PAR protein is a potential target in drug discovery as there are no close homologues of <scene name='82/829351/Parg/1'>PARG</scene>. That’s why there has already been a lot of research concerning novel treatments.<br />
<br />
The goal of searched therapeutics is to find a way to get the protein <scene name='82/829351/Parg/1'>PARG</scene> into a complex that is acting similar to the <scene name='82/829351/Parg/1'>6HMM complex</scene>.Indeed the protein in complex with the anthraquinone does not work properly anymore [http://www.rcsb.org/structure/6HMM], the described complex shows how an inhibited <scene name='82/829351/Parg/1'>PARG</scene> might act in the cell. For now, the research for anthraquinone as inhibitor has stopped as it is cytotoxic for the cell<ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>.<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Laurine Grimandihttps://proteopedia.org/index.php?title=Sandbox_Reserved_1098&diff=3505763Sandbox Reserved 10982022-01-21T19:42:02Z<p>Laurine Grimandi: </p>
<hr />
<div>{{Sandbox_ESBS_2019}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==6HMM== <br />
<StructureSection load='6hmm' size='340' side='right' caption='[[6hmm]]' scene=''><br />
The <scene name='82/829351/6hmm/2'>6HMM protein</scene> is a human[[ poly (ADP-ribose) glycohydrolase]].It is the major enzyme responsible for the catabolism of poly (ADP-ribose), a reversible covalent-modifier of chromosomal proteins. The protein is found in many tissues and may be subject to proteolysis generating smaller, active products.<br />
This protein is only present when the DNA is damaged. It influences the damaged chromatin through a derepression of a gene promoter. Consequently this protein is quite interesting for biotechnological applications. Indeed, knowing the different pathways and protein interactions leading to DNA damage repair is a meaningful goal in research especially in new cancer therapies. <br />
<br />
<br />
=== Catabolism of poly (ADP-ribose) ===<br />
<br />
This protein has four principal domains on a <scene name='82/829351/Single_chain/1'>single peptide chain</scene>: an A-domain, a catalytic domain and two substrate binding domains[http://www.uniprot.org/uniprot/Q86W56]. <br />
The first 456 amino acids of the peptide chain form the <scene name='82/829351/A_domain/1'>A-domain</scene>. Then, from the 610th to the 795th amino acids the <scene name='82/829351/Catalytic_domain/1'>catalytic domain</scene> can be found. This catalytic domain can bind to other proteins with <scene name='82/829351/Substrat_-_catalytic_domain/1'>two amino acids</scene> (the 726th and 727th amino acids). Next, <scene name='82/829351/Subtrat_jonction_domain_2/1'>the second substrate binding domain</scene> is located from the 869th to the 874th amino acid. [http://www.uniprot.org/uniprot/Q86W56]<br />
As such, most of the amino acids form the A-domain and the catalytic domain and only a few amino acids (8 a.a) make links with other proteins. Moreover, the ligand 7JB can bind the protein on the <scene name='82/829351/Liason_7jb/1'>754, 758, 792 and 795 amino acids</scene>. These amino acids are located on a helix and on a beta sheet. [http://www.rcsb.org/pdb/explore/remediatedSequence.do?structureId=6HMM]. There is the <scene name='82/829351/Distritbution_domain/1'>following</scene> amino acid distribution.<br />
<br />
<br />
The protein <scene name='82/829351/Parg/1'>PARG</scene> folds into an ADP-ribose-binding macro domain with an N-terminal extension. It also consists of a diphosphate-binding loop on one side of an ADP-ribose binding cavity. On the other side there are several amino acids matching to the specific <scene name='82/829351/Parg/1'>PARG</scene> signature sequence. <br />
In the macro domain fold, a loop is inserted to welcome the Glu115 side chain protecting the active site of the <scene name='82/829351/Parg/1'>PARG</scene> protein. This loop gives <scene name='82/829351/Parg/1'>PARG</scene> the ability to hydrolyze PAR. The <scene name='82/829351/Parg_active_site/1'>hydrolysis of PAR happens in PARG catalytic domain</scene>. (PAR is represented here in pink).<br />
<br />
=== Post-translational modifications ===<br />
<br />
The protein is a complex composed of the [[ poly (ADP-ribose) glycohydrolase]] (PARG) and the anthraquinone PDD00013907. The Poly(ADP-ribose)glycohydrolase can interact with either [[PCNA]] or [[NUDT5]], this gives various possible functions to the protein. When this protein binds with NUDT5 it can remodel chromatin for example [http://www.uniprot.org/uniprot/Q86W56]. The post-translational modifications of the PAR protein (poly ADP-ribose) are important for DNA stability. <br />
PDD00013907 is, as already stated, an anthraquinone which is a polycyclic aromatic hydrocarbon usually used in biopesticides as a pest repellant. Here it is considered as a free <scene name='82/829351/7jb/1'>ligand</scene> (of identification number on PDB: 7JB) that can bind to the <scene name='82/829351/Parg/1'>PARG</scene> creating the<scene name='82/829351/Complex/1'> protein complex 6HMM</scene>. <br />
<br />
There are several possible post-translational modifications to stabilize DNA. Most commonly there would be phosphorylation, acetylation or methylation <ref>PMID: 21037856</ref>. Another post-translational modification concerning the 6HMM protein is made on the poly(ADP-ribose) protein (PAR). PAR is composed of a repetition of ADP-ribose units linked through glycosidic ribose-ribose bonds <ref>doi: 10.1038/nature10404</ref>. This allows the repair of single-strand breaks on DNA <ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792.">DOI: 10.1021/acs.jmedchem.8b01407</ref>. <scene name='82/829351/Parg/1'>PARG</scene>, a constituent of the <scene name='82/829351/6hmm/1'>6HMM protein</scene> will degrade PAR to allow the <scene name='82/829351/Parp1_on_dna/1'>poly (ADP-ribose) polymerase (PARP)</scene> to free itself from the damaged site, that is now repaired, and completes as such reparation <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12.">PMID: 27689388</ref>.<br />
<br />
The anthraquinone PDD00013907 is a weakly active and cytotoxic anthraquinone 8a acting as a free ligand binding in the ADP-ribose binding site of the <scene name='82/829351/Parg/1'>PARG</scene>. This PDD00013907 should lead to the inhibition of <scene name='82/829351/Parg/1'>PARG</scene>, which is of interest in the search of novel cancer therapies <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. <br />
<br />
=== The mechanism ===<br />
As said previously, poly(ADP-ribosylation) is an important post-translational modification for DNA repair. The mechanism behind this repair relies on several factors. At first, the Poly (ADP-ribose) polymerase (PARP), more specifically the subtype [http://www.uniprot.org/uniprot/P09874 PARP1], will recognize and will bind to the single-stranded break on the DNA. It will then autophosphorylate due to NAD+ and form PAR chains. These will recruit other repair proteins to the site. <br />
<br />
The role of PARG is the hydrolyzation of the specific ribose-ribose bonds present in PAR which leads to its degradation and as such the reparation cycle will be finished<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/>. This degradation is important because without PARG the repair cycle cannot be completed <ref>PMID: 17548475</ref> and may lead to cell death. This is partially due to the still present PARP on the previously damaged site maintained by the non-degraded PAR <ref>PMID: 16140981</ref>. <br />
<br />
== Diseases and Treatment ==<br />
Due to the function of the protein poly (ADP-ribose) glycohydrolase <scene name='82/829351/Parg/1'>PARG</scene> to be part of post-translational processes of DNA damage repair it could be used for new treatments in cancer therapy or for ther diseases. In cancer cells the rate of DNA damage is most probably higher than in normal cells. This could result from the considerably raised stress levels. A deficiency of <scene name='82/829351/Parg/1'>PARG</scene> results in the cessing of the cell cycle and the following cell death<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/><ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. Consequently, the inhibition of <scene name='82/829351/Parg/1'>PARG</scene> might be a solution on how to destroy tumor cells, for example.<br />
<br />
The PAR protein is a potential target in drug discovery as there are no close homologues of <scene name='82/829351/Parg/1'>PARG</scene>. That’s why there has already been a lot of research concerning novel treatments.<br />
<br />
The goal of searched therapeutics is to find a way to get the protein <scene name='82/829351/Parg/1'>PARG</scene> into a complex that is acting similar to the <scene name='82/829351/Parg/1'>6HMM complex</scene>.Indeed the protein in complex with the anthraquinone does not work properly anymore [http://www.rcsb.org/structure/6HMM], the described complex shows how an inhibited PARG might act in the cell. For now, the research for anthraquinone as inhibitor has stopped as it is cytotoxic for the cell<ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>.<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Laurine Grimandihttps://proteopedia.org/index.php?title=Sandbox_Reserved_1098&diff=3505762Sandbox Reserved 10982022-01-21T19:40:11Z<p>Laurine Grimandi: </p>
<hr />
<div>{{Sandbox_ESBS_2019}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==6HMM== <br />
<StructureSection load='6hmm' size='340' side='right' caption='[[6hmm]]' scene=''><br />
The <scene name='82/829351/6hmm/2'>6HMM protein</scene> is a human[[ poly (ADP-ribose) glycohydrolase]].It is the major enzyme responsible for the catabolism of poly (ADP-ribose), a reversible covalent-modifier of chromosomal proteins. The protein is found in many tissues and may be subject to proteolysis generating smaller, active products.<br />
This protein is only present when the DNA is damaged. It influences the damaged chromatin through a derepression of a gene promoter. Consequently this protein is quite interesting for biotechnological applications. Indeed, knowing the different pathways and protein interactions leading to DNA damage repair is a meaningful goal in research especially in new cancer therapies. <br />
<br />
<br />
=== Catabolism of poly (ADP-ribose) ===<br />
<br />
This protein has four principal domains on a <scene name='82/829351/Single_chain/1'>single peptide chain</scene>: an A-domain, a catalytic domain and two substrate binding domains[http://www.uniprot.org/uniprot/Q86W56]. <br />
The first 456 amino acids of the peptide chain form the <scene name='82/829351/A_domain/1'>A-domain</scene>. Then, from the 610th to the 795th amino acids the <scene name='82/829351/Catalytic_domain/1'>catalytic domain</scene> can be found. This catalytic domain can bind to other proteins with <scene name='82/829351/Substrat_-_catalytic_domain/1'>two amino acids</scene> (the 726th and 727th amino acids). Next, <scene name='82/829351/Subtrat_jonction_domain_2/1'>the second substrate binding domain</scene> is located from the 869th to the 874th amino acid. [http://www.uniprot.org/uniprot/Q86W56]<br />
As such, most of the amino acids form the A-domain and the catalytic domain and only a few amino acids (8 a.a) make links with other proteins. Moreover, the ligand 7JB can bind the protein on the <scene name='82/829351/Liason_7jb/1'>754, 758, 792 and 795 amino acids</scene>. These amino acids are located on a helix and on a beta sheet. [http://www.rcsb.org/pdb/explore/remediatedSequence.do?structureId=6HMM]. There is the <scene name='82/829351/Distritbution_domain/1'>following</scene> amino acid distribution.<br />
<br />
<br />
The protein <scene name='82/829351/Parg/1'>PARG</scene> folds into an ADP-ribose-binding macro domain with an N-terminal extension. It also consists of a diphosphate-binding loop on one side of an ADP-ribose binding cavity. On the other side there are several amino acids matching to the specific <scene name='82/829351/Parg/1'>PARG</scene> signature sequence. <br />
In the macro domain fold, a loop is inserted to welcome the Glu115 side chain protecting the active site of the <scene name='82/829351/Parg/1'>PARG</scene> protein. This loop gives <scene name='82/829351/Parg/1'>PARG</scene> the ability to hydrolyze PAR. The <scene name='82/829351/Parg_active_site/1'>hydrolysis of PAR happens in PARG catalytic domain</scene>. (PAR is represented here in pink).<br />
<br />
=== Post-translational modifications ===<br />
<br />
The protein is a complex composed of the [[ poly (ADP-ribose) glycohydrolase]] (PARG) and the anthraquinone PDD00013907. The Poly(ADP-ribose)glycohydrolase can interact with either [[PCNA]] or [[NUDT5]], this gives various possible functions to the protein. When this protein binds with NUDT5 it can remodel chromatin for example [http://www.uniprot.org/uniprot/Q86W56]. The post-translational modifications of the PAR protein (poly ADP-ribose) are important for DNA stability. <br />
PDD00013907 is, as already stated, an anthraquinone which is a polycyclic aromatic hydrocarbon usually used in biopesticides as a pest repellant. Here it is considered as a free <scene name='82/829351/7jb/1'>ligand</scene> (of identification number on PDB: 7JB) that can bind to the <scene name='82/829351/Parg/1'>PARG</scene> creating the<scene name='82/829351/Complex/1'> protein complex 6HMM</scene>. <br />
<br />
There are several possible post-translational modifications to stabilize DNA. Most commonly there would be phosphorylation, acetylation or methylation <ref>PMID: 21037856</ref>. Another post-translational modification concerning the 6HMM protein is made on the poly(ADP-ribose) protein (PAR). PAR is composed of a repetition of ADP-ribose units linked through glycosidic ribose-ribose bonds <ref>doi: 10.1038/nature10404</ref>. This allows the repair of single-strand breaks on DNA <ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792.">DOI: 10.1021/acs.jmedchem.8b01407</ref>. <scene name='82/829351/Parg/1'>PARG</scene>, a constituent of the <scene name='82/829351/6hmm/1'>6HMM protein</scene> will degrade PAR to allow the <scene name='82/829351/Parp1_on_dna/1'>poly (ADP-ribose) polymerase (PARP)</scene> to free itself from the damaged site, that is now repaired, and completes as such reparation <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12.">PMID: 27689388</ref>.<br />
<br />
The anthraquinone PDD00013907 is a weakly active and cytotoxic anthraquinone 8a acting as a free ligand binding in the ADP-ribose binding site of the <scene name='82/829351/Parg/1'>PARG</scene>. This PDD00013907 should lead to the inhibition of <scene name='82/829351/Parg/1'>PARG</scene>, which is of interest in the search of novel cancer therapies <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. <br />
<br />
=== The mechanism ===<br />
As said previously, poly(ADP-ribosylation) is an important post-translational modification for DNA repair. The mechanism behind this repair relies on several factors. At first, the Poly (ADP-ribose) polymerase (PARP), more specifically the subtype [http://www.uniprot.org/uniprot/P09874 PARP1], will recognize and will bind to the single-stranded break on the DNA. It will then autophosphorylate due to NAD+ and form PAR chains. These will recruit other repair proteins to the site. <br />
<br />
The role of PARG is the hydrolyzation of the specific ribose-ribose bonds present in PAR which leads to its degradation and as such the reparation cycle will be finished<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/>. This degradation is important because without PARG the repair cycle cannot be completed <ref>PMID: 17548475</ref> and may lead to cell death. This is partially due to the still present PARP on the previously damaged site maintained by the non-degraded PAR <ref>PMID: 16140981</ref>. <br />
<br />
== Diseases and Treatment ==<br />
Due to the function of the protein poly (ADP-ribose) glycohydrolase <scene name='82/829351/Parg/1'>PARG</scene> to be part of post-translational processes of DNA damage repair it could be used for new treatments in cancer therapy or for ther diseases. In cancer cells the rate of DNA damage is most probably higher than in normal cells. This could result from the considerably raised stress levels. A deficiency of <scene name='82/829351/Parg/1'>PARG</scene> results in the cessing of the cell cycle and the following cell death<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/><ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. Consequently, the inhibition of <scene name='82/829351/Parg/1'>PARG</scene> might be a solution on how to destroy tumor cells, for example.<br />
<br />
The PAR protein is a potential target in drug discovery as there are no close homologues of PARG. That’s why there has already been a lot of research concerning novel treatments.<br />
<br />
The goal of searched therapeutics is to find a way to get the protein <scene name='82/829351/Parg/1'>PARG</scene> into a complex that is acting similar to the <scene name='82/829351/Parg/1'>6HMM complex</scene>.Indeed the protein in complex with the anthraquinone does not work properly anymore [http://www.rcsb.org/structure/6HMM], the described complex shows how an inhibited PARG might act in the cell. For now, the research for anthraquinone as inhibitor has stopped as it is cytotoxic for the cell<ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>.<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Laurine Grimandihttps://proteopedia.org/index.php?title=Sandbox_Reserved_1098&diff=3505761Sandbox Reserved 10982022-01-21T19:31:52Z<p>Laurine Grimandi: </p>
<hr />
<div>{{Sandbox_ESBS_2019}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==6HMM== <br />
<StructureSection load='6hmm' size='340' side='right' caption='[[6hmm]]' scene=''><br />
The <scene name='82/829351/6hmm/2'>6HMM protein</scene> is a human[[ poly (ADP-ribose) glycohydrolase]].It is the major enzyme responsible for the catabolism of poly (ADP-ribose), a reversible covalent-modifier of chromosomal proteins. The protein is found in many tissues and may be subject to proteolysis generating smaller, active products.<br />
This protein is only present when the DNA is damaged. It influences the damaged chromatin through a derepression of a gene promoter. Consequently this protein is quite interesting for biotechnological applications. Indeed, knowing the different pathways and protein interactions leading to DNA damage repair is a meaningful goal in research especially in new cancer therapies. <br />
<br />
<br />
=== Catabolism of poly (ADP-ribose) ===<br />
<br />
This protein has four principal domains on a <scene name='82/829351/Single_chain/1'>single peptide chain</scene>: an A-domain, a catalytic domain and two substrate binding domains[http://www.uniprot.org/uniprot/Q86W56]. <br />
The first 456 amino acids of the peptide chain form the <scene name='82/829351/A_domain/1'>A-domain</scene>. Then, from the 610th to the 795th amino acids the <scene name='82/829351/Catalytic_domain/1'>catalytic domain</scene> can be found. This catalytic domain can bind to other proteins with <scene name='82/829351/Substrat_-_catalytic_domain/1'>two amino acids</scene> (the 726th and 727th amino acids). Next, <scene name='82/829351/Subtrat_jonction_domain_2/1'>the second substrate binding domain</scene> is located from the 869th to the 874th amino acid. [http://www.uniprot.org/uniprot/Q86W56]<br />
As such, most of the amino acids form the A-domain and the catalytic domain and only a few amino acids (8 a.a) make links with other proteins. Moreover, the ligand 7JB can bind the protein on the <scene name='82/829351/Liason_7jb/1'>754, 758, 792 and 795 amino acids</scene>. These amino acids are located on a helix and on a beta sheet. [http://www.rcsb.org/pdb/explore/remediatedSequence.do?structureId=6HMM]. There is the <scene name='82/829351/Distritbution_domain/1'>following</scene> amino acid distribution.<br />
<br />
<br />
The protein <scene name='82/829351/Parg/1'>PARG</scene> folds into an ADP-ribose-binding macro domain with an N-terminal extension. It also consists of a diphosphate-binding loop on one side of an ADP-ribose binding cavity. On the other side there are several amino acids matching to the specific <scene name='82/829351/Parg/1'>PARG</scene> signature sequence. <br />
In the macro domain fold, a loop is inserted to welcome the Glu115 side chain protecting the active site of the <scene name='82/829351/Parg/1'>PARG</scene> protein. This loop gives <scene name='82/829351/Parg/1'>PARG</scene> the ability to hydrolyze PAR. The <scene name='82/829351/Parg_active_site/1'>hydrolysis of PAR happens in PARG catalytic domain</scene>. (PAR is represented here in pink).<br />
<br />
=== Post-translational modifications ===<br />
<br />
The protein is a complex composed of the [[ poly (ADP-ribose) glycohydrolase]] (PARG) and the anthraquinone PDD00013907. The Poly(ADP-ribose)glycohydrolase can interact with either [[PCNA]] or [[NUDT5]], this gives various possible functions to the protein. When this protein binds with NUDT5 it can remodel chromatin for example [http://www.uniprot.org/uniprot/Q86W56]. The post-translational modifications of the PAR protein (poly ADP-ribose) are important for DNA stability. <br />
PDD00013907 is, as already stated, an anthraquinone which is a polycyclic aromatic hydrocarbon usually used in biopesticides as a pest repellant. Here it is considered as a free <scene name='82/829351/7jb/1'>ligand</scene> (of identification number on PDB: 7JB) that can bind to the <scene name='82/829351/Parg/1'>PARG</scene> creating the<scene name='82/829351/Complex/1'> protein complex 6HMM</scene>. <br />
<br />
There are several possible post-translational modifications to stabilize DNA. Most commonly there would be phosphorylation, acetylation or methylation <ref>PMID: 21037856</ref>. Another post-translational modification concerning the 6HMM protein is made on the poly(ADP-ribose) protein (PAR). PAR is composed of a repetition of ADP-ribose units linked through glycosidic ribose-ribose bonds <ref>doi: 10.1038/nature10404</ref>. This allows the repair of single-strand breaks on DNA <ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792.">DOI: 10.1021/acs.jmedchem.8b01407</ref>. <scene name='82/829351/Parg/1'>PARG</scene>, a constituent of the <scene name='82/829351/6hmm/1'>6HMM protein</scene> will degrade PAR to allow the <scene name='82/829351/Parp1_on_dna/1'>poly (ADP-ribose) polymerase (PARP)</scene> to free itself from the damaged site, that is now repaired, and completes as such reparation <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12.">PMID: 27689388</ref>.<br />
<br />
The anthraquinone PDD00013907 is a weakly active and cytotoxic anthraquinone 8a acting as a free ligand binding in the ADP-ribose binding site of the <scene name='82/829351/Parg/1'>PARG</scene>. This PDD00013907 should lead to the inhibition of <scene name='82/829351/Parg/1'>PARG</scene>, which is of interest in the search of novel cancer therapies <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. <br />
<br />
=== The mechanism ===<br />
As said previously, poly(ADP-ribosylation) is an important post-translational modification for DNA repair. The mechanism behind this repair relies on several factors. At first, the Poly (ADP-ribose) polymerase (PARP), more specifically the subtype [http://www.uniprot.org/uniprot/P09874 PARP1], will recognize and will bind to the single-stranded break on the DNA. It will then autophosphorylate due to NAD+ and form PAR chains. These will recruit other repair proteins to the site. <br />
<br />
The role of PARG is the hydrolyzation of the specific ribose-ribose bonds present in PAR which leads to its degradation and as such the reparation cycle will be finished<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/>. This degradation is important because without PARG the repair cycle cannot be completed <ref>PMID: 17548475</ref> and may lead to cell death. This is partially due to the still present PARP on the previously damaged site maintained by the non-degraded PAR <ref>PMID: 16140981</ref>. <br />
<br />
== Diseases and Treatment ==<br />
Due to the function of the protein poly (ADP-ribose) glycohydrolase PARG to be part of post-translational processes of DNA damage repair it could be used for new treatments in cancer therapy or for ther diseases. In cancer cells the rate of DNA damage is most probably higher than in normal cells. This could result from the considerably raised stress levels. A deficiency of PARG results in the cessing of the cell cycle and the following cell death<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/><ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. Consequently, the inhibition of PARG might be a solution on how to destroy tumor cells, for example.<br />
<br />
The PAR protein is a potential target in drug discovery as there are no close homologues of PARG. That’s why there has already been a lot of research concerning novel treatments.<br />
<br />
The goal of searched therapeutics is to find a way to get the protein PARG into a complex that is acting similar to the 6HMM complex.Indeed the protein in complex with the anthraquinone does not work properly anymore [http://www.rcsb.org/structure/6HMM], the described complex shows how an inhibited PARG might act in the cell. For now, the research for anthraquinone as inhibitor has stopped as it is cytotoxic for the cell<ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>.<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Laurine Grimandihttps://proteopedia.org/index.php?title=Sandbox_Reserved_1098&diff=3505760Sandbox Reserved 10982022-01-21T19:29:48Z<p>Laurine Grimandi: </p>
<hr />
<div>{{Sandbox_ESBS_2019}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==6HMM== <br />
<StructureSection load='6hmm' size='340' side='right' caption='[[6hmm]]' scene=''><br />
The <scene name='82/829351/6hmm/2'>6HMM protein</scene> is a human[[ poly (ADP-ribose) glycohydrolase]].It is the major enzyme responsible for the catabolism of poly (ADP-ribose), a reversible covalent-modifier of chromosomal proteins. The protein is found in many tissues and may be subject to proteolysis generating smaller, active products.<br />
This protein is only present when the DNA is damaged. It influences the damaged chromatin through a derepression of a gene promoter. Consequently this protein is quite interesting for biotechnological applications. Indeed, knowing the different pathways and protein interactions leading to DNA damage repair is a meaningful goal in research especially in new cancer therapies. <br />
<br />
<br />
=== Catabolism of poly (ADP-ribose) ===<br />
<br />
This protein has four principal domains on a <scene name='82/829351/Single_chain/1'>single peptide chain</scene>: an A-domain, a catalytic domain and two substrate binding domains[http://www.uniprot.org/uniprot/Q86W56]. <br />
The first 456 amino acids of the peptide chain form the <scene name='82/829351/A_domain/1'>A-domain</scene>. Then, from the 610th to the 795th amino acids the <scene name='82/829351/Catalytic_domain/1'>catalytic domain</scene> can be found. This catalytic domain can bind to other proteins with <scene name='82/829351/Substrat_-_catalytic_domain/1'>two amino acids</scene> (the 726th and 727th amino acids). Next, <scene name='82/829351/Subtrat_jonction_domain_2/1'>the second substrate binding domain</scene> is located from the 869th to the 874th amino acid. [http://www.uniprot.org/uniprot/Q86W56]<br />
As such, most of the amino acids form the A-domain and the catalytic domain and only a few amino acids (8 a.a) make links with other proteins. Moreover, the ligand 7JB can bind the protein on the <scene name='82/829351/Liason_7jb/1'>754, 758, 792 and 795 amino acids</scene>. These amino acids are located on a helix and on a beta sheet. [http://www.rcsb.org/pdb/explore/remediatedSequence.do?structureId=6HMM]. There is the <scene name='82/829351/Distritbution_domain/1'>following</scene> amino acid distribution.<br />
<br />
<br />
The protein <scene name='82/829351/Parg/1'>PARG</scene> folds into an ADP-ribose-binding macro domain with an N-terminal extension. It also consists of a diphosphate-binding loop on one side of an ADP-ribose binding cavity. On the other side there are several amino acids matching to the specific <scene name='82/829351/Parg/1'>PARG</scene> signature sequence. <br />
In the macro domain fold, a loop is inserted to welcome the Glu115 side chain protecting the active site of the <scene name='82/829351/Parg/1'>PARG</scene> protein. This loop gives <scene name='82/829351/Parg/1'>PARG</scene> the ability to hydrolyze PAR. The <scene name='82/829351/Parg_active_site/1'>hydrolysis of PAR happens in PARG catalytic domain</scene>. (PAR is represented here in pink).<br />
<br />
=== Post-translational modifications ===<br />
<br />
The protein is a complex composed of the [[ poly (ADP-ribose) glycohydrolase]] (PARG) and the anthraquinone PDD00013907. The Poly(ADP-ribose)glycohydrolase can interact with either [[PCNA]] or [[NUDT5]], this gives various possible functions to the protein. When this protein binds with NUDT5 it can remodel chromatin for example [http://www.uniprot.org/uniprot/Q86W56]. The post-translational modifications of the PAR protein (poly ADP-ribose) are important for DNA stability. <br />
PDD00013907 is, as already stated, an anthraquinone which is a polycyclic aromatic hydrocarbon usually used in biopesticides as a pest repellant. Here it is considered as a free <scene name='82/829351/7jb/1'>ligand</scene> (of identification number on PDB: 7JB) that can bind to the <scene name='82/829351/Parg/1'>PARG</scene> creating the<scene name='82/829351/Complex/1'> protein complex 6HMM</scene>. <br />
<br />
There are several possible post-translational modifications to stabilize DNA. Most commonly there would be phosphorylation, acetylation or methylation <ref>PMID: 21037856</ref>. Another post-translational modification concerning the 6HMM protein is made on the poly(ADP-ribose) protein (PAR). PAR is composed of a repetition of ADP-ribose units linked through glycosidic ribose-ribose bonds <ref>doi: 10.1038/nature10404</ref>. This allows the repair of single-strand breaks on DNA <ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792.">DOI: 10.1021/acs.jmedchem.8b01407</ref>. <scene name='82/829351/Parg/1'>PARG</scene>, a constituent of the <scene name='82/829351/6hmm/1'>6HMM protein</scene> will degrade PAR to allow the <scene name='82/829351/Parp1_on_dna/1'>poly (ADP-ribose) polymerase (PARP)</scene> to free itself from the damaged site, that is now repaired, and completes as such reparation <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12.">PMID: 27689388</ref>.<br />
<br />
The anthraquinone PDD00013907 is a weakly active and cytotoxic anthraquinone 8a acting as a free ligand binding in the ADP-ribose binding site of the <scene name='82/829351/Parg/1'>PARG</scene>. This PDD00013907 should lead to the inhibition of <scene name='82/829351/Parg/1'>PARG</scene>, which is of interest in the search of novel cancer therapies <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. <br />
<br />
=== The mechanism ===<br />
As said previously, poly(ADP-ribosylation) is an important post-translational modification for DNA repair. The mechanism behind this repair relies on several factors. At first, the Poly (ADP-ribose) polymerase (PARP), more specifically the subtype [http://www.uniprot.org/uniprot/P09874 PARP1], will recognize and will bind to the single-stranded break on the DNA. It will then autophosphorylate due to NAD+ and form PAR chains. These will recruit other repair proteins to the site. <br />
<br />
The role of PARG is the hydrolyzation of the specific ribose-ribose bonds present in PAR which leads to its degradation and as such the reparation cycle will be finished<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/>. This degradation is important because without PARG the repair cycle cannot be completed <ref>PMID: 17548475</ref> and may lead to cell death. This is partially due to the still present PARP on the previously damaged site maintained by the non-degraded PAR <ref>PMID: 16140981</ref>. <br />
<br />
== Diseases and Treatment ==<br />
Due to the function of the protein poly (ADP-ribose) glycohydrolase PARG to be part of post-translational processes of DNA damage repair it could be used for new treatments in cancer therapy or for ther diseases. In cancer cells the rate of DNA damage is most probably higher than in normal cells. This could result from the considerably raised stress levels. A deficiency of PARG results in the cessing of the cell cycle and the following cell death<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/><ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. Consequently, the inhibition of PARG might be a solution on how to destroy tumor cells, for example.<br />
<br />
The PAR protein is a potential target in drug discovery as there are no close homologues of PARG. That’s why there has already been a lot of research concerning novel treatments.<br />
<br />
As the protein in complex with the anthraquinone does not work properly anymore [http://www.rcsb.org/structure/6HMM], the described complex shows how an inhibited PARG might act in the cell. The goal of searched therapeutics is therefore to find a way to get the protein PARG into a complex that is acting similar to the 6HMM complex. For now, the research for anthraquinone as inhibitor has stopped as it is cytotoxic for the cell<ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>.<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Laurine Grimandihttps://proteopedia.org/index.php?title=Sandbox_Reserved_1098&diff=3505759Sandbox Reserved 10982022-01-21T19:28:55Z<p>Laurine Grimandi: </p>
<hr />
<div>{{Sandbox_ESBS_2019}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==6HMM== <br />
<StructureSection load='6hmm' size='340' side='right' caption='[[6hmm]]' scene=''><br />
The <scene name='82/829351/6hmm/2'>6HMM protein</scene> is a human[[ poly (ADP-ribose) glycohydrolase]].It is the major enzyme responsible for the catabolism of poly (ADP-ribose), a reversible covalent-modifier of chromosomal proteins. The protein is found in many tissues and may be subject to proteolysis generating smaller, active products.<br />
This protein is only present when the DNA is damaged. It influences the damaged chromatin through a derepression of a gene promoter. Consequently this protein is quite interesting for biotechnological applications. Indeed, knowing the different pathways and protein interactions leading to DNA damage repair is a meaningful goal in research especially in new cancer therapies. <br />
<br />
<br />
=== Catabolism of poly (ADP-ribose) ===<br />
<br />
This protein has four principal domains on a <scene name='82/829351/Single_chain/1'>single peptide chain</scene>: an A-domain, a catalytic domain and two substrate binding domains[http://www.uniprot.org/uniprot/Q86W56]. <br />
The first 456 amino acids of the peptide chain form the <scene name='82/829351/A_domain/1'>A-domain</scene>. Then, from the 610th to the 795th amino acids the <scene name='82/829351/Catalytic_domain/1'>catalytic domain</scene> can be found. This catalytic domain can bind to other proteins with <scene name='82/829351/Substrat_-_catalytic_domain/1'>two amino acids</scene> (the 726th and 727th amino acids). Next, <scene name='82/829351/Subtrat_jonction_domain_2/1'>the second substrate binding domain</scene> is located from the 869th to the 874th amino acid. [http://www.uniprot.org/uniprot/Q86W56]<br />
As such, most of the amino acids form the A-domain and the catalytic domain and only a few amino acids (8 a.a) make links with other proteins. Moreover, the ligand 7JB can bind the protein on the <scene name='82/829351/Liason_7jb/1'>754, 758, 792 and 795 amino acids</scene>. These amino acids are located on a helix and on a beta sheet. [http://www.rcsb.org/pdb/explore/remediatedSequence.do?structureId=6HMM]. There is the <scene name='82/829351/Distritbution_domain/1'>following</scene> amino acid distribution.<br />
<br />
<br />
The protein <scene name='82/829351/Parg/1'>PARG</scene> folds into an ADP-ribose-binding macro domain with an N-terminal extension. It also consists of a diphosphate-binding loop on one side of an ADP-ribose binding cavity. On the other side there are several amino acids matching to the specific <scene name='82/829351/Parg/1'>PARG</scene> signature sequence. <br />
In the macro domain fold, a loop is inserted to welcome the Glu115 side chain protecting the active site of the <scene name='82/829351/Parg/1'>PARG</scene> protein. This loop gives <scene name='82/829351/Parg/1'>PARG</scene> the ability to hydrolyze PAR. The <scene name='82/829351/Parg_active_site/1'>hydrolysis of PAR happens in PARG catalytic domain</scene>. (PAR is represented here in pink).<br />
<br />
=== Post-translational modifications ===<br />
<br />
The protein is a complex composed of the [[ poly (ADP-ribose) glycohydrolase]] (PARG) and the anthraquinone PDD00013907. The Poly(ADP-ribose)glycohydrolase can interact with either [[PCNA]] or [[NUDT5]], this gives various possible functions to the protein. When this protein binds with NUDT5 it can remodel chromatin for example [http://www.uniprot.org/uniprot/Q86W56]. The post-translational modifications of the PAR protein (poly ADP-ribose) are important for DNA stability. <br />
PDD00013907 is, as already stated, an anthraquinone which is a polycyclic aromatic hydrocarbon usually used in biopesticides as a pest repellant. Here it is considered as a free <scene name='82/829351/7jb/1'>ligand</scene> (of identification number on PDB: 7JB) that can bind to the <scene name='82/829351/Parg/1'>PARG</scene> creating the<scene name='82/829351/Complex/1'> protein complex 6HMM</scene>. <br />
<br />
There are several possible post-translational modifications to stabilize DNA. Most commonly there would be phosphorylation, acetylation or methylation <ref>PMID: 21037856</ref>. Another post-translational modification concerning the 6HMM protein is made on the poly(ADP-ribose) protein (PAR). PAR is composed of a repetition of ADP-ribose units linked through glycosidic ribose-ribose bonds <ref>doi: 10.1038/nature10404</ref>. This allows the repair of single-strand breaks on DNA <ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792.">DOI: 10.1021/acs.jmedchem.8b01407</ref>. <scene name='82/829351/Parg/1'>PARG</scene>, a constituent of the <scene name='82/829351/6hmm/1'>6HMM protein</scene> will degrade PAR to allow the <scene name='82/829351/Parp1_on_dna/1'>poly (ADP-ribose) polymerase (PARP)</scene> to free itself from the damaged site, that is now repaired, and completes as such reparation <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12.">PMID: 27689388</ref>.<br />
<br />
The anthraquinone PDD00013907 is a weakly active and cytotoxic anthraquinone 8a acting as a free ligand binding in the ADP-ribose binding site of the <scene name='82/829351/Parg/1'>PARG</scene>. This PDD00013907 should lead to the inhibition of <scene name='82/829351/Parg/1'>PARG</scene>, which is of interest in the search of novel cancer therapies <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. <br />
<br />
=== The mechanism ===<br />
As said previously, poly(ADP-ribosylation) is an important post-translational modification for DNA repair. The mechanism behind this repair relies on several factors. At first, the Poly (ADP-ribose) polymerase (PARP), more specifically the subtype [http://www.uniprot.org/uniprot/P09874 PARP1], will recognize and will bind to the single-stranded break on the DNA. It will then autophosphorylate due to NAD+ and form PAR chains. These will recruit other repair proteins to the site. <br />
<br />
The role of PARG is the hydrolyzation of the specific ribose-ribose bonds present in PAR which leads to its degradation and as such the reparation cycle will be finished<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/>. This degradation is important because without PARG the repair cycle cannot be completed <ref>PMID: 17548475</ref> and may lead to cell death. This is partially due to the still present PARP on the previously damaged site maintained by the non-degraded PAR <ref>PMID: 16140981</ref>. <br />
<br />
== Diseases and Treatment ==<br />
Due to the function of the protein poly (ADP-ribose) glycohydrolase PARG to be part of post-translational processes of DNA damage repair it could be used for new treatments in cancer therapy or for ther diseases. In cancer cells the rate of DNA damage is most probably higher than in normal cells. This could result from the considerably raised stress levels. A deficiency of PARG results in the cessing of the cell cycle and the following cell death<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/><ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. Consequently, the inhibition of PARG might be a solution on how to destroy tumor cells, for example.<br />
<br />
The PAR protein is a potential target in drug discovery as there are no close homologues of PARG<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ[3] .That’s why there has already been a lot of research concerning novel treatments.<br />
<br />
As the protein in complex with the anthraquinone does not work properly anymore [http://www.rcsb.org/structure/6HMM], the described complex shows how an inhibited PARG might act in the cell. The goal of searched therapeutics is therefore to find a way to get the protein PARG into a complex that is acting similar to the 6HMM complex. For now, the research for anthraquinone as inhibitor has stopped as it is cytotoxic for the cell<ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>.<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Laurine Grimandihttps://proteopedia.org/index.php?title=Sandbox_Reserved_1098&diff=3505758Sandbox Reserved 10982022-01-21T19:26:58Z<p>Laurine Grimandi: </p>
<hr />
<div>{{Sandbox_ESBS_2019}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==6HMM== <br />
<StructureSection load='6hmm' size='340' side='right' caption='[[6hmm]]' scene=''><br />
The <scene name='82/829351/6hmm/2'>6HMM protein</scene> is a human[[ poly (ADP-ribose) glycohydrolase]].It is the major enzyme responsible for the catabolism of poly (ADP-ribose), a reversible covalent-modifier of chromosomal proteins. The protein is found in many tissues and may be subject to proteolysis generating smaller, active products.<br />
This protein is only present when the DNA is damaged. It influences the damaged chromatin through a derepression of a gene promoter. Consequently this protein is quite interesting for biotechnological applications. Indeed, knowing the different pathways and protein interactions leading to DNA damage repair is a meaningful goal in research especially in new cancer therapies. <br />
<br />
<br />
=== Catabolism of poly (ADP-ribose) ===<br />
<br />
This protein has four principal domains on a <scene name='82/829351/Single_chain/1'>single peptide chain</scene>: an A-domain, a catalytic domain and two substrate binding domains[http://www.uniprot.org/uniprot/Q86W56]. <br />
The first 456 amino acids of the peptide chain form the <scene name='82/829351/A_domain/1'>A-domain</scene>. Then, from the 610th to the 795th amino acids the <scene name='82/829351/Catalytic_domain/1'>catalytic domain</scene> can be found. This catalytic domain can bind to other proteins with <scene name='82/829351/Substrat_-_catalytic_domain/1'>two amino acids</scene> (the 726th and 727th amino acids). Next, <scene name='82/829351/Subtrat_jonction_domain_2/1'>the second substrate binding domain</scene> is located from the 869th to the 874th amino acid. [http://www.uniprot.org/uniprot/Q86W56]<br />
As such, most of the amino acids form the A-domain and the catalytic domain and only a few amino acids (8 a.a) make links with other proteins. Moreover, the ligand 7JB can bind the protein on the <scene name='82/829351/Liason_7jb/1'>754, 758, 792 and 795 amino acids</scene>. These amino acids are located on a helix and on a beta sheet. [http://www.rcsb.org/pdb/explore/remediatedSequence.do?structureId=6HMM]. There is the <scene name='82/829351/Distritbution_domain/1'>following</scene> amino acid distribution.<br />
<br />
<br />
The protein <scene name='82/829351/Parg/1'>PARG</scene> folds into an ADP-ribose-binding macro domain with an N-terminal extension. It also consists of a diphosphate-binding loop on one side of an ADP-ribose binding cavity. On the other side there are several amino acids matching to the specific <scene name='82/829351/Parg/1'>PARG</scene> signature sequence. <br />
In the macro domain fold, a loop is inserted to welcome the Glu115 side chain protecting the active site of the <scene name='82/829351/Parg/1'>PARG</scene> protein. This loop gives <scene name='82/829351/Parg/1'>PARG</scene> the ability to hydrolyze PAR. The <scene name='82/829351/Parg_active_site/1'>hydrolysis of PAR happens in PARG catalytic domain</scene>. (PAR is represented here in pink).<br />
<br />
=== Post-translational modifications ===<br />
<br />
The protein is a complex composed of the [[ poly (ADP-ribose) glycohydrolase]] (PARG) and the anthraquinone PDD00013907. The Poly(ADP-ribose)glycohydrolase can interact with either [[PCNA]] or [[NUDT5]], this gives various possible functions to the protein. When this protein binds with NUDT5 it can remodel chromatin for example [http://www.uniprot.org/uniprot/Q86W56]. The post-translational modifications of the PAR protein (poly ADP-ribose) are important for DNA stability. <br />
PDD00013907 is, as already stated, an anthraquinone which is a polycyclic aromatic hydrocarbon usually used in biopesticides as a pest repellant. Here it is considered as a free <scene name='82/829351/7jb/1'>ligand</scene> (of identification number on PDB: 7JB) that can bind to the <scene name='82/829351/Parg/1'>PARG</scene> creating the<scene name='82/829351/Complex/1'> protein complex 6HMM</scene>. <br />
<br />
There are several possible post-translational modifications to stabilize DNA. Most commonly there would be phosphorylation, acetylation or methylation <ref>PMID: 21037856</ref>. Another post-translational modification concerning the 6HMM protein is made on the poly(ADP-ribose) protein (PAR). PAR is composed of a repetition of ADP-ribose units linked through glycosidic ribose-ribose bonds <ref>doi: 10.1038/nature10404</ref>. This allows the repair of single-strand breaks on DNA <ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792.">DOI: 10.1021/acs.jmedchem.8b01407</ref>. <scene name='82/829351/Parg/1'>PARG</scene>, a constituent of the <scene name='82/829351/6hmm/1'>6HMM protein</scene> will degrade PAR to allow the <scene name='82/829351/Parp1_on_dna/1'>poly (ADP-ribose) polymerase (PARP)</scene> to free itself from the damaged site, that is now repaired, and completes as such reparation <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12.">PMID: 27689388</ref>.<br />
<br />
The anthraquinone PDD00013907 is a weakly active and cytotoxic anthraquinone 8a acting as a free ligand binding in the ADP-ribose binding site of the <scene name='82/829351/Parg/1'>PARG</scene>. This PDD00013907 should lead to the inhibition of <scene name='82/829351/Parg/1'>PARG</scene>, which is of interest in the search of novel cancer therapies <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. <br />
<br />
=== The mechanism ===<br />
As said previously, poly(ADP-ribosylation) is an important post-translational modification for DNA repair. The mechanism behind this repair relies on several factors. At first, the Poly (ADP-ribose) polymerase (PARP), more specifically the subtype [http://www.uniprot.org/uniprot/P09874 PARP1], will recognize and will bind to the single-stranded break on the DNA. It will then autophosphorylate due to NAD+ and form PAR chains. These will recruit other repair proteins to the site. <br />
<br />
The role of PARG is the hydrolyzation of the specific ribose-ribose bonds present in PAR which leads to its degradation and as such the reparation cycle will be finished<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/>. This degradation is important because without PARG the repair cycle cannot be completed <ref>PMID: 17548475</ref> and may lead to cell death. This is partially due to the still present PARP on the previously damaged site maintained by the non-degraded PAR <ref>PMID: 16140981</ref>. <br />
<br />
== Diseases and Treatment ==<br />
Due to the function of the protein poly (ADP-ribose) glycohydrolase PARG to be part of post-translational processes of DNA damage repair it could be used for new treatments in cancer therapy or for ther diseases. In cancer cells the rate of DNA damage is most probably higher than in normal cells. This could result from the considerably raised stress levels. A deficiency of PARG results in the cessing of the cell cycle and the following cell death<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/><ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. Consequently, the inhibition of PARG might be a solution on how to destroy tumor cells, for example.<br />
<br />
The PAR protein is a potential target in drug discovery as there are no close homologues of PARG[3] .That’s why there has already been a lot of research concerning novel treatments.<br />
<br />
As the protein in complex with the anthraquinone does not work properly anymore [http://www.rcsb.org/structure/6HMM], the described complex shows how an inhibited PARG might act in the cell. The goal of searched therapeutics is therefore to find a way to get the protein PARG into a complex that is acting similar to the 6HMM complex. For now, the research for anthraquinone as inhibitor has stopped as it is cytotoxic for the cell<ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>.<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Laurine Grimandihttps://proteopedia.org/index.php?title=Sandbox_Reserved_1098&diff=3505754Sandbox Reserved 10982022-01-21T19:08:50Z<p>Laurine Grimandi: </p>
<hr />
<div>{{Sandbox_ESBS_2019}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==6HMM== <br />
<StructureSection load='6hmm' size='340' side='right' caption='[[6hmm]]' scene=''><br />
The <scene name='82/829351/6hmm/2'>6HMM protein</scene> is a human[[ poly (ADP-ribose) glycohydrolase]].It is the major enzyme responsible for the catabolism of poly (ADP-ribose), a reversible covalent-modifier of chromosomal proteins. The protein is found in many tissues and may be subject to proteolysis generating smaller, active products.<br />
This protein is only present when the DNA is damaged. It influences the damaged chromatin through a derepression of a gene promoter. Consequently this protein is quite interesting for biotechnological applications. Indeed, knowing the different pathways and protein interactions leading to DNA damage repair is a meaningful goal in research especially in new cancer therapies. <br />
<br />
<br />
=== Catabolism of poly (ADP-ribose) ===<br />
<br />
This protein has four principal domains on a <scene name='82/829351/Single_chain/1'>single peptide chain</scene>: an A-domain, a catalytic domain and two substrate binding domains[http://www.uniprot.org/uniprot/Q86W56]. <br />
The first 456 amino acids of the peptide chain form the <scene name='82/829351/A_domain/1'>A-domain</scene>. Then, from the 610th to the 795th amino acids the <scene name='82/829351/Catalytic_domain/1'>catalytic domain</scene> can be found. This catalytic domain can bind to other proteins with <scene name='82/829351/Substrat_-_catalytic_domain/1'>two amino acids</scene> (the 726th and 727th amino acids). Next, <scene name='82/829351/Subtrat_jonction_domain_2/1'>the second substrate binding domain</scene> is located from the 869th to the 874th amino acid. [http://www.uniprot.org/uniprot/Q86W56]<br />
As such, most of the amino acids form the A-domain and the catalytic domain and only a few amino acids (8 a.a) make links with other proteins. Moreover, the ligand 7JB can bind the protein on the <scene name='82/829351/Liason_7jb/1'>754, 758, 792 and 795 amino acids</scene>. These amino acids are located on a helix and on a beta sheet. [http://www.rcsb.org/pdb/explore/remediatedSequence.do?structureId=6HMM]. There is the <scene name='82/829351/Distritbution_domain/1'>following</scene> amino acid distribution.<br />
<br />
<br />
The protein <scene name='82/829351/Parg/1'>PARG</scene> folds into an ADP-ribose-binding macro domain with an N-terminal extension. It also consists of a diphosphate-binding loop on one side of an ADP-ribose binding cavity. On the other side there are several amino acids matching to the specific <scene name='82/829351/Parg/1'>PARG</scene> signature sequence. <br />
In the macro domain fold, a loop is inserted to welcome the Glu115 side chain protecting the active site of the <scene name='82/829351/Parg/1'>PARG</scene> protein. This loop gives <scene name='82/829351/Parg/1'>PARG</scene> the ability to hydrolyze PAR. The <scene name='82/829351/Parg_active_site/1'>hydrolysis of PAR happens in PARG catalytic domain</scene>. (PAR is represented here in pink).<br />
<br />
=== Post-translational modifications ===<br />
<br />
The protein is a complex composed of the [[ poly (ADP-ribose) glycohydrolase]] (PARG) and the anthraquinone PDD00013907. The Poly(ADP-ribose)glycohydrolase can interact with either [[PCNA]] or [[NUDT5]], this gives various possible functions to the protein. When this protein binds with NUDT5 it can remodel chromatin for example [http://www.uniprot.org/uniprot/Q86W56]. The post-translational modifications of the PAR protein (poly ADP-ribose) are important for DNA stability. <br />
PDD00013907 is, as already stated, an anthraquinone which is a polycyclic aromatic hydrocarbon usually used in biopesticides as a pest repellant. Here it is considered as a free <scene name='82/829351/7jb/1'>ligand</scene> (of identification number on PDB: 7JB) that can bind to the <scene name='82/829351/Parg/1'>PARG</scene> creating the<scene name='82/829351/Complex/1'> protein complex 6HMM</scene>. <br />
<br />
There are several possible post-translational modifications to stabilize DNA. Most commonly there would be phosphorylation, acetylation or methylation <ref>PMID: 21037856</ref>. Another post-translational modification concerning the 6HMM protein is made on the poly(ADP-ribose) protein (PAR). PAR is composed of a repetition of ADP-ribose units linked through glycosidic ribose-ribose bonds <ref>doi: 10.1038/nature10404</ref>. This allows the repair of single-strand breaks on DNA <ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792.">DOI: 10.1021/acs.jmedchem.8b01407</ref>. <scene name='82/829351/Parg/1'>PARG</scene>, a constituent of the <scene name='82/829351/6hmm/1'>6HMM protein</scene> will degrade PAR to allow the <scene name='82/829351/Parp1_on_dna/1'>poly (ADP-ribose) polymerase (PARP)</scene> to free itself from the damaged site, that is now repaired, and completes as such reparation <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12.">PMID: 27689388</ref>.<br />
<br />
The anthraquinone PDD00013907 is a weakly active and cytotoxic anthraquinone 8a acting as a free ligand binding in the ADP-ribose binding site of the <scene name='82/829351/Parg/1'>PARG</scene>. This PDD00013907 should lead to the inhibition of <scene name='82/829351/Parg/1'>PARG</scene>, which is of interest in the search of novel cancer therapies <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. <br />
<br />
=== The mechanism ===<br />
As said previously, poly(ADP-ribosylation) is an important post-translational modification for DNA repair. The mechanism behind this repair relies on several factors. At first, the Poly (ADP-ribose) polymerase (PARP), more specifically the subtype [http://www.uniprot.org/uniprot/P09874 PARP1], will recognize and will bind to the single-stranded break on the DNA. It will then autophosphorylate due to NAD+ and form PAR chains. These will recruit other repair proteins to the site. <br />
<br />
The role of PARG is the hydrolyzation of the specific ribose-ribose bonds present in PAR which leads to its degradation and as such the reparation cycle will be finished<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/>. This degradation is important because without PARG the repair cycle cannot be completed <ref>PMID: 17548475</ref> and may lead to cell death. This is partially due to the still present PARP on the previously damaged site maintained by the non-degraded PAR <ref>PMID: 16140981</ref>. <br />
<br />
== Diseases and Relevance ==<br />
Due to the function of the protein poly (ADP-ribose) glycohydrolase PARG to be part of post-translational processes of DNA damage repair it could be used for new treatments in cancer therapy or for ther diseases. In cancer cells the rate of DNA damage is most probably higher than in normal cells. This could result from the considerably raised stress levels. A deficiency of PARG results in the cessing of the cell cycle and the following cell death<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/><ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. Consequently, the inhibition of PARG might be a solution on how to destroy tumor cells, for example.<br />
<br />
For the PAR protein, there has already been a lot of research concerning novel treatments, but not for PARG. As there are no close homologues of PARG<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/>, this protein provides a potential target in drug discovery.<br />
<br />
As the protein in complex with the anthraquinone does not work properly anymore [http://www.rcsb.org/structure/6HMM], the described complex shows how an inhibited PARG might act in the cell. The goal of searched therapeutics is therefore to find a way to get the protein PARG into a complex that is acting similar to the 6HMM complex. For now, the research for anthraquinone as inhibitor has stopped as it is cytotoxic for the cell<ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>.<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Laurine Grimandihttps://proteopedia.org/index.php?title=Sandbox_Reserved_1098&diff=3505753Sandbox Reserved 10982022-01-21T19:07:35Z<p>Laurine Grimandi: </p>
<hr />
<div>{{Sandbox_ESBS_2019}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==6HMM== <br />
<StructureSection load='6hmm' size='340' side='right' caption='[[6hmm]]' scene=''><br />
The <scene name='82/829351/6hmm/2'>6HMM protein</scene> is a human[[ poly (ADP-ribose) glycohydrolase]].It is the major enzyme responsible for the catabolism of poly (ADP-ribose), a reversible covalent-modifier of chromosomal proteins. The protein is found in many tissues and may be subject to proteolysis generating smaller, active products.<br />
This protein is only present when the DNA is damaged. It influences the damaged chromatin through a derepression of a gene promoter. Consequently this protein is quite interesting for biotechnological applications. Indeed, knowing the different pathways and protein interactions leading to DNA damage repair is a meaningful goal in research especially in new cancer therapies. <br />
<br />
<br />
=== Catabolism of poly (ADP-ribose) ===<br />
<br />
This protein has four principal domains on a <scene name='82/829351/Single_chain/1'>single peptide chain</scene>: an A-domain, a catalytic domain and two substrate binding domains[http://www.uniprot.org/uniprot/Q86W56]. <br />
The first 456 amino acids of the peptide chain form the <scene name='82/829351/A_domain/1'>A-domain</scene>. Then, from the 610th to the 795th amino acids the <scene name='82/829351/Catalytic_domain/1'>catalytic domain</scene> can be found. This catalytic domain can bind to other proteins with <scene name='82/829351/Substrat_-_catalytic_domain/1'>two amino acids</scene> (the 726th and 727th amino acids). Next, <scene name='82/829351/Subtrat_jonction_domain_2/1'>the second substrate binding domain</scene> is located from the 869th to the 874th amino acid. [http://www.uniprot.org/uniprot/Q86W56]<br />
As such, most of the amino acids form the A-domain and the catalytic domain and only a few amino acids (8 a.a) make links with other proteins. Moreover, the ligand 7JB can bind the protein on the <scene name='82/829351/Liason_7jb/1'>754, 758, 792 and 795 amino acids</scene>. These amino acids are located on a helix and on a beta sheet. [http://www.rcsb.org/pdb/explore/remediatedSequence.do?structureId=6HMM]. There is the <scene name='82/829351/Distritbution_domain/1'>following</scene> amino acid distribution.<br />
<br />
<br />
The protein <scene name='82/829351/Parg/1'>PARG</scene> folds into an ADP-ribose-binding macro domain with an N-terminal extension. It also consists of a diphosphate-binding loop on one side of an ADP-ribose binding cavity. On the other side there are several amino acids matching to the specific <scene name='82/829351/Parg/1'>PARG</scene> signature sequence. <br />
In the macro domain fold, a loop is inserted to welcome the Glu115 side chain protecting the active site of the <scene name='82/829351/Parg/1'>PARG</scene> protein. This loop gives <scene name='82/829351/Parg/1'>PARG</scene> the ability to hydrolyze PAR. The <scene name='82/829351/Parg_active_site/1'>hydrolysis of PAR happens in PARG catalytic domain</scene>. (PAR is represented here in pink).<br />
<br />
=== Post-translational modifications ===<br />
<br />
The protein is a complex composed of the [[ poly (ADP-ribose) glycohydrolase]] (PARG) and the anthraquinone PDD00013907. The Poly(ADP-ribose)glycohydrolase can interact with either [[PCNA]] or [[NUDT5]], this gives various possible functions to the protein. When this protein binds with NUDT5 it can remodel chromatin for example [http://www.uniprot.org/uniprot/Q86W56]. The post-translational modifications of the PAR protein (poly ADP-ribose) are important for DNA stability. <br />
PDD00013907 is, as already stated, an anthraquinone which is a polycyclic aromatic hydrocarbon usually used in biopesticides as a pest repellant. Here it is considered as a free <scene name='82/829351/7jb/1'>ligand</scene> (of identification number on PDB: 7JB) that can bind to the <scene name='82/829351/Parg/1'>PARG</scene> creating the<scene name='82/829351/Complex/1'> protein complex 6HMM</scene>. <br />
<br />
There are several possible post-translational modifications to stabilize DNA. Most commonly there would be phosphorylation, acetylation or methylation <ref>PMID: 21037856</ref>. Another post-translational modification concerning the 6HMM protein is made on the poly(ADP-ribose) protein (PAR). PAR is composed of a repetition of ADP-ribose units linked through glycosidic ribose-ribose bonds <ref>doi: 10.1038/nature10404</ref>. This allows the repair of single-strand breaks on DNA <ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792.">DOI: 10.1021/acs.jmedchem.8b01407</ref>. <scene name='82/829351/Parg/1'>PARG</scene>, a constituent of the <scene name='82/829351/6hmm/1'>6HMM protein</scene> will degrade PAR to allow the <scene name='82/829351/Parp1_on_dna/1'>poly (ADP-ribose) polymerase (PARP)</scene> to free itself from the damaged site, that is now repaired, and completes as such reparation <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12.">PMID: 27689388</ref>.<br />
<br />
The anthraquinone PDD00013907 is a weakly active and cytotoxic anthraquinone 8a acting as a free ligand binding in the ADP-ribose binding site of the <scene name='82/829351/Parg/1'>PARG</scene>. This PDD00013907 should lead to the inhibition of PARG, which is of interest in the search of novel cancer therapies <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. <br />
<br />
=== The mechanism ===<br />
As said previously, poly(ADP-ribosylation) is an important post-translational modification for DNA repair. The mechanism behind this repair relies on several factors. At first, the Poly (ADP-ribose) polymerase (PARP), more specifically the subtype [http://www.uniprot.org/uniprot/P09874 PARP1], will recognize and will bind to the single-stranded break on the DNA. It will then autophosphorylate due to NAD+ and form PAR chains. These will recruit other repair proteins to the site. <br />
<br />
The role of PARG is the hydrolyzation of the specific ribose-ribose bonds present in PAR which leads to its degradation and as such the reparation cycle will be finished<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/>. This degradation is important because without PARG the repair cycle cannot be completed <ref>PMID: 17548475</ref> and may lead to cell death. This is partially due to the still present PARP on the previously damaged site maintained by the non-degraded PAR <ref>PMID: 16140981</ref>. <br />
<br />
== Diseases and Relevance ==<br />
Due to the function of the protein poly (ADP-ribose) glycohydrolase PARG to be part of post-translational processes of DNA damage repair it could be used for new treatments in cancer therapy or for ther diseases. In cancer cells the rate of DNA damage is most probably higher than in normal cells. This could result from the considerably raised stress levels. A deficiency of PARG results in the cessing of the cell cycle and the following cell death<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/><ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. Consequently, the inhibition of PARG might be a solution on how to destroy tumor cells, for example.<br />
<br />
For the PAR protein, there has already been a lot of research concerning novel treatments, but not for PARG. As there are no close homologues of PARG<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/>, this protein provides a potential target in drug discovery.<br />
<br />
As the protein in complex with the anthraquinone does not work properly anymore [http://www.rcsb.org/structure/6HMM], the described complex shows how an inhibited PARG might act in the cell. The goal of searched therapeutics is therefore to find a way to get the protein PARG into a complex that is acting similar to the 6HMM complex. For now, the research for anthraquinone as inhibitor has stopped as it is cytotoxic for the cell<ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>.<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Laurine Grimandihttps://proteopedia.org/index.php?title=Sandbox_Reserved_1098&diff=3505752Sandbox Reserved 10982022-01-21T19:06:26Z<p>Laurine Grimandi: </p>
<hr />
<div>{{Sandbox_ESBS_2019}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==6HMM== <br />
<StructureSection load='6hmm' size='340' side='right' caption='[[6hmm]]' scene=''><br />
The <scene name='82/829351/6hmm/2'>6HMM protein</scene> is a human[[ poly (ADP-ribose) glycohydrolase]].It is the major enzyme responsible for the catabolism of poly (ADP-ribose), a reversible covalent-modifier of chromosomal proteins. The protein is found in many tissues and may be subject to proteolysis generating smaller, active products.<br />
This protein is only present when the DNA is damaged. It influences the damaged chromatin through a derepression of a gene promoter. Consequently this protein is quite interesting for biotechnological applications. Indeed, knowing the different pathways and protein interactions leading to DNA damage repair is a meaningful goal in research especially in new cancer therapies. <br />
<br />
<br />
=== Catabolism of poly (ADP-ribose) ===<br />
<br />
This protein has four principal domains on a <scene name='82/829351/Single_chain/1'>single peptide chain</scene>: an A-domain, a catalytic domain and two substrate binding domains[http://www.uniprot.org/uniprot/Q86W56]. <br />
The first 456 amino acids of the peptide chain form the <scene name='82/829351/A_domain/1'>A-domain</scene>. Then, from the 610th to the 795th amino acids the <scene name='82/829351/Catalytic_domain/1'>catalytic domain</scene> can be found. This catalytic domain can bind to other proteins with <scene name='82/829351/Substrat_-_catalytic_domain/1'>two amino acids</scene> (the 726th and 727th amino acids). Next, <scene name='82/829351/Subtrat_jonction_domain_2/1'>the second substrate binding domain</scene> is located from the 869th to the 874th amino acid. [http://www.uniprot.org/uniprot/Q86W56]<br />
As such, most of the amino acids form the A-domain and the catalytic domain and only a few amino acids (8 a.a) make links with other proteins. Moreover, the ligand 7JB can bind the protein on the <scene name='82/829351/Liason_7jb/1'>754, 758, 792 and 795 amino acids</scene>. These amino acids are located on a helix and on a beta sheet. [http://www.rcsb.org/pdb/explore/remediatedSequence.do?structureId=6HMM]. There is the <scene name='82/829351/Distritbution_domain/1'>following</scene> amino acid distribution.<br />
<br />
<br />
The protein <scene name='82/829351/Parg/1'>PARG</scene> folds into an ADP-ribose-binding macro domain with an N-terminal extension. It also consists of a diphosphate-binding loop on one side of an ADP-ribose binding cavity. On the other side there are several amino acids matching to the specific <scene name='82/829351/Parg/1'>PARG</scene> signature sequence. <br />
In the macro domain fold, a loop is inserted to welcome the Glu115 side chain protecting the active site of the <scene name='82/829351/Parg/1'>PARG</scene> protein. This loop gives <scene name='82/829351/Parg/1'>PARG</scene> the ability to hydrolyze PAR. The <scene name='82/829351/Parg_active_site/1'>hydrolysis of PAR happens in PARG catalytic domain</scene>. (PAR is represented here in pink).<br />
<br />
=== Post-translational modifications ===<br />
<br />
The protein is a complex composed of the [[ poly (ADP-ribose) glycohydrolase]] (PARG) and the anthraquinone PDD00013907. The Poly(ADP-ribose)glycohydrolase can interact with either [[PCNA]] or [[NUDT5]], this gives various possible functions to the protein. When this protein binds with NUDT5 it can remodel chromatin for example [http://www.uniprot.org/uniprot/Q86W56]. The post-translational modifications of the PAR protein (poly ADP-ribose) are important for DNA stability. <br />
PDD00013907 is, as already stated, an anthraquinone which is a polycyclic aromatic hydrocarbon usually used in biopesticides as a pest repellant. Here it is considered as a free <scene name='82/829351/7jb/1'>ligand</scene> (of identification number on PDB: 7JB) that can bind to the <scene name='82/829351/Parg/1'>PARG</scene> creating the<scene name='82/829351/Complex/1'> protein complex 6HMM</scene>. <br />
<br />
There are several possible post-translational modifications to stabilize DNA. Most commonly there would be phosphorylation, acetylation or methylation <ref>PMID: 21037856</ref>. Another post-translational modification concerning the 6HMM protein is made on the poly(ADP-ribose) protein (PAR). PAR is composed of a repetition of ADP-ribose units linked through glycosidic ribose-ribose bonds <ref>doi: 10.1038/nature10404</ref>. This allows the repair of single-strand breaks on DNA <ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792.">DOI: 10.1021/acs.jmedchem.8b01407</ref>. <scene name='82/829351/Parg/1'>PARG</scene>, a constituent of the <scene name='82/829351/6hmm/1'>6HMM protein</scene> will degrade PAR to allow the <scene name='82/829351/Parp1_on_dna/1'>poly (ADP-ribose) polymerase (PARP)</scene> to free itself from the damaged site, that is now repaired, and completes as such reparation <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12.">PMID: 27689388</ref>.<br />
<br />
The anthraquinone PDD00013907 is a weakly active and cytotoxic anthraquinone 8a acting as a free ligand binding in the ADP-ribose binding site of the PARG. This PDD00013907 should lead to the inhibition of PARG, which is of interest in the search of novel cancer therapies <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. <br />
<br />
=== The mechanism ===<br />
As said previously, poly(ADP-ribosylation) is an important post-translational modification for DNA repair. The mechanism behind this repair relies on several factors. At first, the Poly (ADP-ribose) polymerase (PARP), more specifically the subtype [http://www.uniprot.org/uniprot/P09874 PARP1], will recognize and will bind to the single-stranded break on the DNA. It will then autophosphorylate due to NAD+ and form PAR chains. These will recruit other repair proteins to the site. <br />
<br />
The role of PARG is the hydrolyzation of the specific ribose-ribose bonds present in PAR which leads to its degradation and as such the reparation cycle will be finished<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/>. This degradation is important because without PARG the repair cycle cannot be completed <ref>PMID: 17548475</ref> and may lead to cell death. This is partially due to the still present PARP on the previously damaged site maintained by the non-degraded PAR <ref>PMID: 16140981</ref>. <br />
<br />
== Diseases and Relevance ==<br />
Due to the function of the protein poly (ADP-ribose) glycohydrolase PARG to be part of post-translational processes of DNA damage repair it could be used for new treatments in cancer therapy or for ther diseases. In cancer cells the rate of DNA damage is most probably higher than in normal cells. This could result from the considerably raised stress levels. A deficiency of PARG results in the cessing of the cell cycle and the following cell death<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/><ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. Consequently, the inhibition of PARG might be a solution on how to destroy tumor cells, for example.<br />
<br />
For the PAR protein, there has already been a lot of research concerning novel treatments, but not for PARG. As there are no close homologues of PARG<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/>, this protein provides a potential target in drug discovery.<br />
<br />
As the protein in complex with the anthraquinone does not work properly anymore [http://www.rcsb.org/structure/6HMM], the described complex shows how an inhibited PARG might act in the cell. The goal of searched therapeutics is therefore to find a way to get the protein PARG into a complex that is acting similar to the 6HMM complex. For now, the research for anthraquinone as inhibitor has stopped as it is cytotoxic for the cell<ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>.<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Laurine Grimandihttps://proteopedia.org/index.php?title=Sandbox_Reserved_1098&diff=3505751Sandbox Reserved 10982022-01-21T19:04:52Z<p>Laurine Grimandi: </p>
<hr />
<div>{{Sandbox_ESBS_2019}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==6HMM== <br />
<StructureSection load='6hmm' size='340' side='right' caption='[[6hmm]]' scene=''><br />
The <scene name='82/829351/6hmm/2'>6HMM protein</scene> is a human[[ poly (ADP-ribose) glycohydrolase]].It is the major enzyme responsible for the catabolism of poly (ADP-ribose), a reversible covalent-modifier of chromosomal proteins. The protein is found in many tissues and may be subject to proteolysis generating smaller, active products.<br />
This protein is only present when the DNA is damaged. It influences the damaged chromatin through a derepression of a gene promoter. Consequently this protein is quite interesting for biotechnological applications. Indeed, knowing the different pathways and protein interactions leading to DNA damage repair is a meaningful goal in research especially in new cancer therapies. <br />
<br />
<br />
=== Catabolism of poly (ADP-ribose) ===<br />
<br />
This protein has four principal domains on a <scene name='82/829351/Single_chain/1'>single peptide chain</scene>: an A-domain, a catalytic domain and two substrate binding domains[http://www.uniprot.org/uniprot/Q86W56]. <br />
The first 456 amino acids of the peptide chain form the <scene name='82/829351/A_domain/1'>A-domain</scene>. Then, from the 610th to the 795th amino acids the <scene name='82/829351/Catalytic_domain/1'>catalytic domain</scene> can be found. This catalytic domain can bind to other proteins with <scene name='82/829351/Substrat_-_catalytic_domain/1'>two amino acids</scene> (the 726th and 727th amino acids). Next, <scene name='82/829351/Subtrat_jonction_domain_2/1'>the second substrate binding domain</scene> is located from the 869th to the 874th amino acid. [http://www.uniprot.org/uniprot/Q86W56]<br />
As such, most of the amino acids form the A-domain and the catalytic domain and only a few amino acids (8 a.a) make links with other proteins. Moreover, the ligand 7JB can bind the protein on the <scene name='82/829351/Liason_7jb/1'>754, 758, 792 and 795 amino acids</scene>. These amino acids are located on a helix and on a beta sheet. [http://www.rcsb.org/pdb/explore/remediatedSequence.do?structureId=6HMM]. There is the <scene name='82/829351/Distritbution_domain/1'>following</scene> amino acid distribution.<br />
<br />
<br />
The protein <scene name='82/829351/Parg/1'>PARG</scene> folds into an ADP-ribose-binding macro domain with an N-terminal extension. It also consists of a diphosphate-binding loop on one side of an ADP-ribose binding cavity. On the other side there are several amino acids matching to the specific <scene name='82/829351/Parg/1'>PARG</scene> signature sequence. <br />
In the macro domain fold, a loop is inserted to welcome the Glu115 side chain protecting the active site of the <scene name='82/829351/Parg/1'>PARG</scene> protein. This loop gives <scene name='82/829351/Parg/1'>PARG</scene> the ability to hydrolyze PAR. The <scene name='82/829351/Parg_active_site/1'>hydrolysis of PAR happens in PARG catalytic domain</scene>. (PAR is represented here in pink).<br />
<br />
=== Post-translational modifications ===<br />
<br />
The protein is a complex composed of the [[ poly (ADP-ribose) glycohydrolase]] (PARG) and the anthraquinone PDD00013907. The Poly(ADP-ribose)glycohydrolase can interact with either [[PCNA]] or [[NUDT5]], this gives various possible functions to the protein. When this protein binds with NUDT5 it can remodel chromatin for example [http://www.uniprot.org/uniprot/Q86W56]. The post-translational modifications of the PAR protein (poly ADP-ribose) are important for DNA stability. <br />
PDD00013907 is, as already stated, an anthraquinone which is a polycyclic aromatic hydrocarbon usually used in biopesticides as a pest repellant. Here it is considered as a free <scene name='82/829351/7jb/1'>ligand</scene> (of identification number on PDB: 7JB) that can bind to the <scene name='82/829351/Parg/1'>PARG</scene> creating the<scene name='82/829351/Complex/1'> protein complex 6HMM</scene>. <br />
<br />
There are several possible post-translational modifications to stabilize DNA. Most commonly there would be phosphorylation, acetylation or methylation <ref>PMID: 21037856</ref>. Another post-translational modification concerning the 6HMM protein is made on the poly(ADP-ribose) protein (PAR). PAR is composed of a repetition of ADP-ribose units linked through glycosidic ribose-ribose bonds <ref>doi: 10.1038/nature10404</ref>. This allows the repair of single-strand breaks on DNA <ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792.">DOI: 10.1021/acs.jmedchem.8b01407</ref>. PARG, a constituent of the <scene name='82/829351/6hmm/1'>6HMM protein</scene> will degrade PAR to allow the <scene name='82/829351/Parp1_on_dna/1'>poly (ADP-ribose) polymerase (PARP)</scene> to free itself from the damaged site, that is now repaired, and completes as such reparation <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12.">PMID: 27689388</ref>.<br />
<br />
The anthraquinone PDD00013907 is a weakly active and cytotoxic anthraquinone 8a acting as a free ligand binding in the ADP-ribose binding site of the PARG. This PDD00013907 should lead to the inhibition of PARG, which is of interest in the search of novel cancer therapies <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. <br />
<br />
=== The mechanism ===<br />
As said previously, poly(ADP-ribosylation) is an important post-translational modification for DNA repair. The mechanism behind this repair relies on several factors. At first, the Poly (ADP-ribose) polymerase (PARP), more specifically the subtype [http://www.uniprot.org/uniprot/P09874 PARP1], will recognize and will bind to the single-stranded break on the DNA. It will then autophosphorylate due to NAD+ and form PAR chains. These will recruit other repair proteins to the site. <br />
<br />
The role of PARG is the hydrolyzation of the specific ribose-ribose bonds present in PAR which leads to its degradation and as such the reparation cycle will be finished<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/>. This degradation is important because without PARG the repair cycle cannot be completed <ref>PMID: 17548475</ref> and may lead to cell death. This is partially due to the still present PARP on the previously damaged site maintained by the non-degraded PAR <ref>PMID: 16140981</ref>. <br />
<br />
== Diseases and Relevance ==<br />
Due to the function of the protein poly (ADP-ribose) glycohydrolase PARG to be part of post-translational processes of DNA damage repair it could be used for new treatments in cancer therapy or for ther diseases. In cancer cells the rate of DNA damage is most probably higher than in normal cells. This could result from the considerably raised stress levels. A deficiency of PARG results in the cessing of the cell cycle and the following cell death<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/><ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. Consequently, the inhibition of PARG might be a solution on how to destroy tumor cells, for example.<br />
<br />
For the PAR protein, there has already been a lot of research concerning novel treatments, but not for PARG. As there are no close homologues of PARG<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/>, this protein provides a potential target in drug discovery.<br />
<br />
As the protein in complex with the anthraquinone does not work properly anymore [http://www.rcsb.org/structure/6HMM], the described complex shows how an inhibited PARG might act in the cell. The goal of searched therapeutics is therefore to find a way to get the protein PARG into a complex that is acting similar to the 6HMM complex. For now, the research for anthraquinone as inhibitor has stopped as it is cytotoxic for the cell<ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>.<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Laurine Grimandihttps://proteopedia.org/index.php?title=Sandbox_Reserved_1098&diff=3505722Sandbox Reserved 10982022-01-21T10:38:58Z<p>Laurine Grimandi: </p>
<hr />
<div>{{Sandbox_ESBS_2019}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==6HMM== <br />
<StructureSection load='6hmm' size='340' side='right' caption='[[6hmm]]' scene=''><br />
The <scene name='82/829351/6hmm/2'>6HMM protein</scene> is a human[[ poly (ADP-ribose) glycohydrolase]].It is the major enzyme responsible for the catabolism of poly (ADP-ribose), a reversible covalent-modifier of chromosomal proteins. The protein is found in many tissues and may be subject to proteolysis generating smaller, active products.<br />
This protein is only present when the DNA is damaged. It influences the damaged chromatin through a derepression of a gene promoter. Consequently this protein is quite interesting for biotechnological applications. Indeed, knowing the different pathways and protein interactions leading to DNA damage repair is a meaningful goal in research especially in new cancer therapies. <br />
<br />
<br />
=== Catabolism of poly (ADP-ribose) ===<br />
<br />
This protein has four principal domains on a <scene name='82/829351/Single_chain/1'>single peptide chain</scene>: an A-domain, a catalytic domain and two substrate binding domains[http://www.uniprot.org/uniprot/Q86W56]. <br />
The first 456 amino acids of the peptide chain form the <scene name='82/829351/A_domain/1'>A-domain</scene>. Then, from the 610th to the 795th amino acids the <scene name='82/829351/Catalytic_domain/1'>catalytic domain</scene> can be found. This catalytic domain can bind to other proteins with <scene name='82/829351/Substrat_-_catalytic_domain/1'>two amino acids</scene> (the 726th and 727th amino acids). Next, <scene name='82/829351/Subtrat_jonction_domain_2/1'>the second substrate binding domain</scene> is located from the 869th to the 874th amino acid. [http://www.uniprot.org/uniprot/Q86W56]<br />
As such, most of the amino acids form the A-domain and the catalytic domain and only a few amino acids (8 a.a) make links with other proteins. Moreover, the ligand 7JB can bind the protein on the <scene name='82/829351/Liason_7jb/1'>754, 758, 792 and 795 amino acids</scene>. These amino acids are located on a helix and on a beta sheet. [http://www.rcsb.org/pdb/explore/remediatedSequence.do?structureId=6HMM]. There is the <scene name='82/829351/Distritbution_domain/1'>following</scene> amino acid distribution.<br />
<br />
<br />
The protein <scene name='82/829351/Parg/1'>PARG</scene> folds into an ADP-ribose-binding macro domain with an N-terminal extension. It also consists of a diphosphate-binding loop on one side of an ADP-ribose binding cavity. On the other side there are several amino acids matching to the specific <scene name='82/829351/Parg/1'>PARG</scene> signature sequence. <br />
In the macro domain fold, a loop is inserted to welcome the Glu115 side chain protecting the active site of the <scene name='82/829351/Parg/1'>PARG</scene> protein. This loop gives <scene name='82/829351/Parg/1'>PARG</scene> the ability to hydrolyze PAR. The <scene name='82/829351/Parg_active_site/1'>hydrolysis of PAR happens in PARG catalytic domain</scene>. (PAR is represented here in pink).<br />
<br />
=== Post-translational modifications ===<br />
<br />
The protein is a complex composed of the [[ poly (ADP-ribose) glycohydrolase]] (PARG) and the anthraquinone PDD00013907. The Poly(ADP-ribose)glycohydrolase can interact with either [[PCNA]] or [[NUDT5]], this gives various possible functions to the protein. When this protein binds with NUDT5 it can remodel chromatin for example [http://www.uniprot.org/uniprot/Q86W56]. The post-translational modifications of the PAR protein (poly ADP-ribose) are important for DNA stability. <br />
PDD00013907 is, as already stated, an anthraquinone which is a polycyclic aromatic hydrocarbon usually used in biopesticides as a pest repellant. Here it is considered as a free <scene name='82/829351/7jb/1'>ligand</scene> (of identification number on PDB: 7JB) that can bind to the <scene name='82/829351/Parg/1'>PARG</scene> creating the<scene name='82/829351/Complex/1'> protein complex 6HMM</scene>. <br />
<br />
There are several possible post-translational modifications to stabilize DNA. Most commonly there would be phosphorylation, acetylation or methylation <ref>PMID: 21037856</ref>. Another post-translational modification concerning the 6HMM protein is made on the poly(ADP-ribose) protein (PAR). PAR is composed of a repetition of ADP-ribose units linked through glycosidic ribose-ribose bonds <ref>doi: 10.1038/nature10404</ref>. This allows the repair of single-strand breaks on DNA <ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792.">DOI: 10.1021/acs.jmedchem.8b01407</ref>. PARG, a constituent of the 6HMM protein, will degrade PAR to allow the <scene name='82/829351/Parp1_on_dna/1'>poly (ADP-ribose) polymerase (PARP)</scene> to free itself from the damaged site, that is now repaired, and completes as such reparation <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12.">PMID: 27689388</ref>.<br />
<br />
The anthraquinone PDD00013907 is a weakly active and cytotoxic anthraquinone 8a acting as a free ligand binding in the ADP-ribose binding site of the PARG. This PDD00013907 should lead to the inhibition of PARG, which is of interest in the search of novel cancer therapies <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. <br />
<br />
=== The mechanism ===<br />
As said previously, poly(ADP-ribosylation) is an important post-translational modification for DNA repair. The mechanism behind this repair relies on several factors. At first, the Poly (ADP-ribose) polymerase (PARP), more specifically the subtype [http://www.uniprot.org/uniprot/P09874 PARP1], will recognize and will bind to the single-stranded break on the DNA. It will then autophosphorylate due to NAD+ and form PAR chains. These will recruit other repair proteins to the site. <br />
<br />
The role of PARG is the hydrolyzation of the specific ribose-ribose bonds present in PAR which leads to its degradation and as such the reparation cycle will be finished<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/>. This degradation is important because without PARG the repair cycle cannot be completed <ref>PMID: 17548475</ref> and may lead to cell death. This is partially due to the still present PARP on the previously damaged site maintained by the non-degraded PAR <ref>PMID: 16140981</ref>. <br />
<br />
== Diseases and Relevance ==<br />
Due to the function of the protein poly (ADP-ribose) glycohydrolase PARG to be part of post-translational processes of DNA damage repair it could be used for new treatments in cancer therapy or for ther diseases. In cancer cells the rate of DNA damage is most probably higher than in normal cells. This could result from the considerably raised stress levels. A deficiency of PARG results in the cessing of the cell cycle and the following cell death<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/><ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. Consequently, the inhibition of PARG might be a solution on how to destroy tumor cells, for example.<br />
<br />
For the PAR protein, there has already been a lot of research concerning novel treatments, but not for PARG. As there are no close homologues of PARG<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/>, this protein provides a potential target in drug discovery.<br />
<br />
As the protein in complex with the anthraquinone does not work properly anymore [http://www.rcsb.org/structure/6HMM], the described complex shows how an inhibited PARG might act in the cell. The goal of searched therapeutics is therefore to find a way to get the protein PARG into a complex that is acting similar to the 6HMM complex. For now, the research for anthraquinone as inhibitor has stopped as it is cytotoxic for the cell<ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>.<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Laurine Grimandihttps://proteopedia.org/index.php?title=Sandbox_Reserved_1098&diff=3505721Sandbox Reserved 10982022-01-21T10:36:08Z<p>Laurine Grimandi: </p>
<hr />
<div>{{Sandbox_ESBS_2019}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==6HMM== <br />
<StructureSection load='6hmm' size='340' side='right' caption='[[6hmm]]' scene=''><br />
The <scene name='82/829351/6hmm/2'>6HMM protein</scene> is a human[[ poly (ADP-ribose) glycohydrolase]].It is the major enzyme responsible for the catabolism of poly (ADP-ribose), a reversible covalent-modifier of chromosomal proteins. The protein is found in many tissues and may be subject to proteolysis generating smaller, active products.<br />
This protein is only present when the DNA is damaged. It influences the damaged chromatin through a derepression of a gene promoter. Consequently this protein is quite interesting for biotechnological applications. Indeed, knowing the different pathways and protein interactions leading to DNA damage repair is a meaningful goal in research especially in new cancer therapies. <br />
<br />
<br />
=== Catabolism of poly (ADP-ribose) ===<br />
<br />
This protein has four principal domains on a <scene name='82/829351/Single_chain/1'>single peptide chain</scene>: an A-domain, a catalytic domain and two substrate binding domains[http://www.uniprot.org/uniprot/Q86W56]. <br />
The first 456 amino acids of the peptide chain form the <scene name='82/829351/A_domain/1'>A-domain</scene>. Then, from the 610th to the 795th amino acids the <scene name='82/829351/Catalytic_domain/1'>catalytic domain</scene> can be found. This catalytic domain can bind to other proteins with <scene name='82/829351/Substrat_-_catalytic_domain/1'>two amino acids</scene> (the 726th and 727th amino acids). Next, <scene name='82/829351/Subtrat_jonction_domain_2/1'>the second substrate binding domain</scene> is located from the 869th to the 874th amino acid. [http://www.uniprot.org/uniprot/Q86W56]<br />
As such, most of the amino acids form the A-domain and the catalytic domain and only a few amino acids (8 a.a) make links with other proteins. Moreover, the ligand 7JB can bind the protein on the <scene name='82/829351/Liason_7jb/1'>754, 758, 792 and 795 amino acids</scene>. These amino acids are located on a helix and on a beta sheet. [http://www.rcsb.org/pdb/explore/remediatedSequence.do?structureId=6HMM]. There is the <scene name='82/829351/Distritbution_domain/1'>following</scene> amino acid distribution.<br />
<br />
<br />
The protein <scene name='82/829351/Parg/1'>PARG</scene> folds into an ADP-ribose-binding macro domain with an N-terminal extension. It also consists of a diphosphate-binding loop on one side of an ADP-ribose binding cavity. On the other side there are several amino acids matching to the specific <scene name='82/829351/Parg/1'>PARG</scene> signature sequence. <br />
In the macro domain fold, a loop is inserted to welcome the Glu115 side chain protecting the active site of the <scene name='82/829351/Parg/1'>PARG</scene> protein. This loop gives PARG the ability to hydrolyze PAR. The <scene name='82/829351/Parg_active_site/1'>hydrolysis of PAR happens in PARG catalytic domain</scene>. (PAR is represented here in pink).<br />
<br />
=== Post-translational modifications ===<br />
<br />
The protein is a complex composed of the [[ poly (ADP-ribose) glycohydrolase]] (PARG) and the anthraquinone PDD00013907. The Poly(ADP-ribose)glycohydrolase can interact with either [[PCNA]] or [[NUDT5]], this gives various possible functions to the protein. When this protein binds with NUDT5 it can remodel chromatin for example [http://www.uniprot.org/uniprot/Q86W56]. The post-translational modifications of the PAR protein (poly ADP-ribose) are important for DNA stability. <br />
PDD00013907 is, as already stated, an anthraquinone which is a polycyclic aromatic hydrocarbon usually used in biopesticides as a pest repellant. Here it is considered as a free <scene name='82/829351/7jb/1'>ligand</scene> (of identification number on PDB: 7JB) that can bind to the <scene name='82/829351/Parg/1'>PARG</scene> creating the<scene name='82/829351/Complex/1'> protein complex 6HMM</scene>. <br />
<br />
There are several possible post-translational modifications to stabilize DNA. Most commonly there would be phosphorylation, acetylation or methylation <ref>PMID: 21037856</ref>. Another post-translational modification concerning the 6HMM protein is made on the poly(ADP-ribose) protein (PAR). PAR is composed of a repetition of ADP-ribose units linked through glycosidic ribose-ribose bonds <ref>doi: 10.1038/nature10404</ref>. This allows the repair of single-strand breaks on DNA <ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792.">DOI: 10.1021/acs.jmedchem.8b01407</ref>. PARG, a constituent of the 6HMM protein, will degrade PAR to allow the <scene name='82/829351/Parp1_on_dna/1'>poly (ADP-ribose) polymerase (PARP)</scene> to free itself from the damaged site, that is now repaired, and completes as such reparation <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12.">PMID: 27689388</ref>.<br />
<br />
The anthraquinone PDD00013907 is a weakly active and cytotoxic anthraquinone 8a acting as a free ligand binding in the ADP-ribose binding site of the PARG. This PDD00013907 should lead to the inhibition of PARG, which is of interest in the search of novel cancer therapies <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. <br />
<br />
=== The mechanism ===<br />
As said previously, poly(ADP-ribosylation) is an important post-translational modification for DNA repair. The mechanism behind this repair relies on several factors. At first, the Poly (ADP-ribose) polymerase (PARP), more specifically the subtype [http://www.uniprot.org/uniprot/P09874 PARP1], will recognize and will bind to the single-stranded break on the DNA. It will then autophosphorylate due to NAD+ and form PAR chains. These will recruit other repair proteins to the site. <br />
<br />
The role of PARG is the hydrolyzation of the specific ribose-ribose bonds present in PAR which leads to its degradation and as such the reparation cycle will be finished<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/>. This degradation is important because without PARG the repair cycle cannot be completed <ref>PMID: 17548475</ref> and may lead to cell death. This is partially due to the still present PARP on the previously damaged site maintained by the non-degraded PAR <ref>PMID: 16140981</ref>. <br />
<br />
== Diseases and Relevance ==<br />
Due to the function of the protein poly (ADP-ribose) glycohydrolase PARG to be part of post-translational processes of DNA damage repair it could be used for new treatments in cancer therapy or for ther diseases. In cancer cells the rate of DNA damage is most probably higher than in normal cells. This could result from the considerably raised stress levels. A deficiency of PARG results in the cessing of the cell cycle and the following cell death<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/><ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. Consequently, the inhibition of PARG might be a solution on how to destroy tumor cells, for example.<br />
<br />
For the PAR protein, there has already been a lot of research concerning novel treatments, but not for PARG. As there are no close homologues of PARG<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/>, this protein provides a potential target in drug discovery.<br />
<br />
As the protein in complex with the anthraquinone does not work properly anymore [http://www.rcsb.org/structure/6HMM], the described complex shows how an inhibited PARG might act in the cell. The goal of searched therapeutics is therefore to find a way to get the protein PARG into a complex that is acting similar to the 6HMM complex. For now, the research for anthraquinone as inhibitor has stopped as it is cytotoxic for the cell<ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>.<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Laurine Grimandihttps://proteopedia.org/index.php?title=Sandbox_Reserved_1098&diff=3505720Sandbox Reserved 10982022-01-21T10:34:54Z<p>Laurine Grimandi: </p>
<hr />
<div>{{Sandbox_ESBS_2019}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==6HMM== <br />
<StructureSection load='6hmm' size='340' side='right' caption='[[6hmm]]' scene=''><br />
The <scene name='82/829351/6hmm/2'>6HMM protein</scene> is a human[[ poly (ADP-ribose) glycohydrolase]].It is the major enzyme responsible for the catabolism of poly (ADP-ribose), a reversible covalent-modifier of chromosomal proteins. The protein is found in many tissues and may be subject to proteolysis generating smaller, active products.<br />
This protein is only present when the DNA is damaged. It influences the damaged chromatin through a derepression of a gene promoter. Consequently this protein is quite interesting for biotechnological applications. Indeed, knowing the different pathways and protein interactions leading to DNA damage repair is a meaningful goal in research especially in new cancer therapies. <br />
<br />
<br />
=== Catabolism of poly (ADP-ribose) ===<br />
<br />
This protein has four principal domains on a <scene name='82/829351/Single_chain/1'>single peptide chain</scene>: an A-domain, a catalytic domain and two substrate binding domains[http://www.uniprot.org/uniprot/Q86W56]. <br />
The first 456 amino acids of the peptide chain form the <scene name='82/829351/A_domain/1'>A-domain</scene>. Then, from the 610th to the 795th amino acids the <scene name='82/829351/Catalytic_domain/1'>catalytic domain</scene> can be found. This catalytic domain can bind to other proteins with <scene name='82/829351/Substrat_-_catalytic_domain/1'>two amino acids</scene> (the 726th and 727th amino acids). Next, <scene name='82/829351/Subtrat_jonction_domain_2/1'>the second substrate binding domain</scene> is located from the 869th to the 874th amino acid. [http://www.uniprot.org/uniprot/Q86W56]<br />
As such, most of the amino acids form the A-domain and the catalytic domain and only a few amino acids (8 a.a) make links with other proteins. Moreover, the ligand 7JB can bind the protein on the <scene name='82/829351/Liason_7jb/1'>754, 758, 792 and 795 amino acids</scene>. These amino acids are located on a helix and on a beta sheet. [http://www.rcsb.org/pdb/explore/remediatedSequence.do?structureId=6HMM]. There is the <scene name='82/829351/Distritbution_domain/1'>following</scene> amino acid distribution.<br />
<br />
<br />
The protein <scene name='82/829351/Parg/1'>PARG</scene> folds into an ADP-ribose-binding macro domain with an N-terminal extension. It also consists of a diphosphate-binding loop on one side of an ADP-ribose binding cavity. On the other side there are several amino acids matching to the specific PARG signature sequence. <br />
In the macro domain fold, a loop is inserted to welcome the Glu115 side chain protecting the active site of the <scene name='82/829351/Parg/1'>PARG</scene> protein. This loop gives PARG the ability to hydrolyze PAR. The <scene name='82/829351/Parg_active_site/1'>hydrolysis of PAR happens in PARG catalytic domain</scene>. (PAR is represented here in pink).<br />
<br />
=== Post-translational modifications ===<br />
<br />
The protein is a complex composed of the [[ poly (ADP-ribose) glycohydrolase]] (PARG) and the anthraquinone PDD00013907. The Poly(ADP-ribose)glycohydrolase can interact with either [[PCNA]] or [[NUDT5]], this gives various possible functions to the protein. When this protein binds with NUDT5 it can remodel chromatin for example [http://www.uniprot.org/uniprot/Q86W56]. The post-translational modifications of the PAR protein (poly ADP-ribose) are important for DNA stability. <br />
PDD00013907 is, as already stated, an anthraquinone which is a polycyclic aromatic hydrocarbon usually used in biopesticides as a pest repellant. Here it is considered as a free <scene name='82/829351/7jb/1'>ligand</scene> (of identification number on PDB: 7JB) that can bind to the <scene name='82/829351/Parg/1'>PARG</scene> creating the<scene name='82/829351/Complex/1'> protein complex 6HMM</scene>. <br />
<br />
There are several possible post-translational modifications to stabilize DNA. Most commonly there would be phosphorylation, acetylation or methylation <ref>PMID: 21037856</ref>. Another post-translational modification concerning the 6HMM protein is made on the poly(ADP-ribose) protein (PAR). PAR is composed of a repetition of ADP-ribose units linked through glycosidic ribose-ribose bonds <ref>doi: 10.1038/nature10404</ref>. This allows the repair of single-strand breaks on DNA <ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792.">DOI: 10.1021/acs.jmedchem.8b01407</ref>. PARG, a constituent of the 6HMM protein, will degrade PAR to allow the <scene name='82/829351/Parp1_on_dna/1'>poly (ADP-ribose) polymerase (PARP)</scene> to free itself from the damaged site, that is now repaired, and completes as such reparation <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12.">PMID: 27689388</ref>.<br />
<br />
The anthraquinone PDD00013907 is a weakly active and cytotoxic anthraquinone 8a acting as a free ligand binding in the ADP-ribose binding site of the PARG. This PDD00013907 should lead to the inhibition of PARG, which is of interest in the search of novel cancer therapies <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. <br />
<br />
=== The mechanism ===<br />
As said previously, poly(ADP-ribosylation) is an important post-translational modification for DNA repair. The mechanism behind this repair relies on several factors. At first, the Poly (ADP-ribose) polymerase (PARP), more specifically the subtype [http://www.uniprot.org/uniprot/P09874 PARP1], will recognize and will bind to the single-stranded break on the DNA. It will then autophosphorylate due to NAD+ and form PAR chains. These will recruit other repair proteins to the site. <br />
<br />
The role of PARG is the hydrolyzation of the specific ribose-ribose bonds present in PAR which leads to its degradation and as such the reparation cycle will be finished<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/>. This degradation is important because without PARG the repair cycle cannot be completed <ref>PMID: 17548475</ref> and may lead to cell death. This is partially due to the still present PARP on the previously damaged site maintained by the non-degraded PAR <ref>PMID: 16140981</ref>. <br />
<br />
== Diseases and Relevance ==<br />
Due to the function of the protein poly (ADP-ribose) glycohydrolase PARG to be part of post-translational processes of DNA damage repair it could be used for new treatments in cancer therapy or for ther diseases. In cancer cells the rate of DNA damage is most probably higher than in normal cells. This could result from the considerably raised stress levels. A deficiency of PARG results in the cessing of the cell cycle and the following cell death<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/><ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. Consequently, the inhibition of PARG might be a solution on how to destroy tumor cells, for example.<br />
<br />
For the PAR protein, there has already been a lot of research concerning novel treatments, but not for PARG. As there are no close homologues of PARG<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/>, this protein provides a potential target in drug discovery.<br />
<br />
As the protein in complex with the anthraquinone does not work properly anymore [http://www.rcsb.org/structure/6HMM], the described complex shows how an inhibited PARG might act in the cell. The goal of searched therapeutics is therefore to find a way to get the protein PARG into a complex that is acting similar to the 6HMM complex. For now, the research for anthraquinone as inhibitor has stopped as it is cytotoxic for the cell<ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>.<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Laurine Grimandihttps://proteopedia.org/index.php?title=Sandbox_Reserved_1098&diff=3505719Sandbox Reserved 10982022-01-21T10:33:46Z<p>Laurine Grimandi: </p>
<hr />
<div>{{Sandbox_ESBS_2019}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==6HMM== <br />
<StructureSection load='6hmm' size='340' side='right' caption='[[6hmm]]' scene=''><br />
The <scene name='82/829351/6hmm/2'>6HMM protein</scene> is a human[[ poly (ADP-ribose) glycohydrolase]].It is the major enzyme responsible for the catabolism of poly (ADP-ribose), a reversible covalent-modifier of chromosomal proteins. The protein is found in many tissues and may be subject to proteolysis generating smaller, active products.<br />
This protein is only present when the DNA is damaged. It influences the damaged chromatin through a derepression of a gene promoter. Consequently this protein is quite interesting for biotechnological applications. Indeed, knowing the different pathways and protein interactions leading to DNA damage repair is a meaningful goal in research especially in new cancer therapies. <br />
<br />
<br />
=== Catabolism of poly (ADP-ribose) ===<br />
<br />
This protein has four principal domains on a <scene name='82/829351/Single_chain/1'>single peptide chain</scene>: an A-domain, a catalytic domain and two substrate binding domains[http://www.uniprot.org/uniprot/Q86W56]. <br />
The first 456 amino acids of the peptide chain form the <scene name='82/829351/A_domain/1'>A-domain</scene>. Then, from the 610th to the 795th amino acids the <scene name='82/829351/Catalytic_domain/1'>catalytic domain</scene> can be found. This catalytic domain can bind to other proteins with <scene name='82/829351/Substrat_-_catalytic_domain/1'>two amino acids</scene> (the 726th and 727th amino acids). Next, <scene name='82/829351/Subtrat_jonction_domain_2/1'>the second substrate binding domain</scene> is located from the 869th to the 874th amino acid. [http://www.uniprot.org/uniprot/Q86W56]<br />
As such, most of the amino acids form the A-domain and the catalytic domain and only a few amino acids (8 a.a) make links with other proteins. Moreover, the ligand 7JB can bind the protein on the <scene name='82/829351/Liason_7jb/1'>754, 758, 792 and 795 amino acids</scene>. These amino acids are located on a helix and on a beta sheet. [http://www.rcsb.org/pdb/explore/remediatedSequence.do?structureId=6HMM]. There is the <scene name='82/829351/Distritbution_domain/1'>following</scene> amino acid distribution.<br />
<br />
<br />
The protein <scene name='82/829351/Parg/1'>PARG</scene> folds into an ADP-ribose-binding macro domain with an N-terminal extension. It also consists of a diphosphate-binding loop on one side of an ADP-ribose binding cavity. On the other side there are several amino acids matching to the specific PARG signature sequence. <br />
In the macro domain fold, a loop is inserted to welcome the Glu115 side chain protecting the active site of the <scene name='82/829351/Parg/1'>PARG</scene>protein. This loop gives PARG the ability to hydrolyze PAR. The <scene name='82/829351/Parg_active_site/1'>hydrolysis of PAR happens in PARG catalytic domain</scene>. (PAR is represented here in pink).<br />
<br />
=== Post-translational modifications ===<br />
<scene name='82/829351/Parg/1'>Part</scene><br />
<br />
The protein is a complex composed of the [[ poly (ADP-ribose) glycohydrolase]] (PARG) and the anthraquinone PDD00013907. The Poly(ADP-ribose)glycohydrolase can interact with either [[PCNA]] or [[NUDT5]], this gives various possible functions to the protein. When this protein binds with NUDT5 it can remodel chromatin for example [http://www.uniprot.org/uniprot/Q86W56]. The post-translational modifications of the PAR protein (poly ADP-ribose) are important for DNA stability. <br />
PDD00013907 is, as already stated, an anthraquinone which is a polycyclic aromatic hydrocarbon usually used in biopesticides as a pest repellant. Here it is considered as a free <scene name='82/829351/7jb/1'>ligand</scene> (of identification number on PDB: 7JB) that can bind to the <scene name='82/829351/Parg/1'>PARG</scene> creating the<scene name='82/829351/Complex/1'> protein complex 6HMM</scene>. <br />
<br />
There are several possible post-translational modifications to stabilize DNA. Most commonly there would be phosphorylation, acetylation or methylation <ref>PMID: 21037856</ref>. Another post-translational modification concerning the 6HMM protein is made on the poly(ADP-ribose) protein (PAR). PAR is composed of a repetition of ADP-ribose units linked through glycosidic ribose-ribose bonds <ref>doi: 10.1038/nature10404</ref>. This allows the repair of single-strand breaks on DNA <ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792.">DOI: 10.1021/acs.jmedchem.8b01407</ref>. PARG, a constituent of the 6HMM protein, will degrade PAR to allow the <scene name='82/829351/Parp1_on_dna/1'>poly (ADP-ribose) polymerase (PARP)</scene> to free itself from the damaged site, that is now repaired, and completes as such reparation <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12.">PMID: 27689388</ref>.<br />
<br />
The anthraquinone PDD00013907 is a weakly active and cytotoxic anthraquinone 8a acting as a free ligand binding in the ADP-ribose binding site of the PARG. This PDD00013907 should lead to the inhibition of PARG, which is of interest in the search of novel cancer therapies <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. <br />
<br />
=== The mechanism ===<br />
As said previously, poly(ADP-ribosylation) is an important post-translational modification for DNA repair. The mechanism behind this repair relies on several factors. At first, the Poly (ADP-ribose) polymerase (PARP), more specifically the subtype [http://www.uniprot.org/uniprot/P09874 PARP1], will recognize and will bind to the single-stranded break on the DNA. It will then autophosphorylate due to NAD+ and form PAR chains. These will recruit other repair proteins to the site. <br />
<br />
The role of PARG is the hydrolyzation of the specific ribose-ribose bonds present in PAR which leads to its degradation and as such the reparation cycle will be finished<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/>. This degradation is important because without PARG the repair cycle cannot be completed <ref>PMID: 17548475</ref> and may lead to cell death. This is partially due to the still present PARP on the previously damaged site maintained by the non-degraded PAR <ref>PMID: 16140981</ref>. <br />
<br />
== Diseases and Relevance ==<br />
Due to the function of the protein poly (ADP-ribose) glycohydrolase PARG to be part of post-translational processes of DNA damage repair it could be used for new treatments in cancer therapy or for ther diseases. In cancer cells the rate of DNA damage is most probably higher than in normal cells. This could result from the considerably raised stress levels. A deficiency of PARG results in the cessing of the cell cycle and the following cell death<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/><ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. Consequently, the inhibition of PARG might be a solution on how to destroy tumor cells, for example.<br />
<br />
For the PAR protein, there has already been a lot of research concerning novel treatments, but not for PARG. As there are no close homologues of PARG<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/>, this protein provides a potential target in drug discovery.<br />
<br />
As the protein in complex with the anthraquinone does not work properly anymore [http://www.rcsb.org/structure/6HMM], the described complex shows how an inhibited PARG might act in the cell. The goal of searched therapeutics is therefore to find a way to get the protein PARG into a complex that is acting similar to the 6HMM complex. For now, the research for anthraquinone as inhibitor has stopped as it is cytotoxic for the cell<ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>.<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Laurine Grimandihttps://proteopedia.org/index.php?title=Sandbox_Reserved_1098&diff=3500189Sandbox Reserved 10982022-01-11T21:34:23Z<p>Laurine Grimandi: </p>
<hr />
<div>{{Sandbox_ESBS_2019}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==6HMM== <br />
<StructureSection load='6hmm' size='340' side='right' caption='[[6hmm]]' scene=''><br />
The <scene name='82/829351/6hmm/2'>6HMM protein</scene> is a human[[ poly (ADP-ribose) glycohydrolase]].It is the major enzyme responsible for the catabolism of poly (ADP-ribose), a reversible covalent-modifier of chromosomal proteins. The protein is found in many tissues and may be subject to proteolysis generating smaller, active products.<br />
This protein is only present when the DNA is damaged. It influences the damaged chromatin through a derepression of a gene promoter. Consequently this protein is quite interesting for biotechnological applications. Indeed, knowing the different pathways and protein interactions leading to DNA damage repair is a meaningful goal in research especially in new cancer therapies. <br />
<br />
<br />
=== Catabolism of poly (ADP-ribose) ===<br />
<br />
This protein has four principal domains on a <scene name='82/829351/Single_chain/1'>single peptide chain</scene>: an A-domain, a catalytic domain and two substrate binding domains[http://www.uniprot.org/uniprot/Q86W56]. <br />
The first 456 amino acids of the peptide chain form the <scene name='82/829351/A_domain/1'>A-domain</scene>. Then, from the 610th to the 795th amino acids the <scene name='82/829351/Catalytic_domain/1'>catalytic domain</scene> can be found. This catalytic domain can bind to other proteins with <scene name='82/829351/Substrat_-_catalytic_domain/1'>two amino acids</scene> (the 726th and 727th amino acids). Next, <scene name='82/829351/Subtrat_jonction_domain_2/1'>the second substrate binding domain</scene> is located from the 869th to the 874th amino acid. [http://www.uniprot.org/uniprot/Q86W56]<br />
As such, most of the amino acids form the A-domain and the catalytic domain and only a few amino acids (8 a.a) make links with other proteins. Moreover, the ligand 7JB can bind the protein on the <scene name='82/829351/Liason_7jb/1'>754, 758, 792 and 795 amino acids</scene>. These amino acids are located on a helix and on a beta sheet. [http://www.rcsb.org/pdb/explore/remediatedSequence.do?structureId=6HMM]. There is the <scene name='82/829351/Distritbution_domain/1'>following</scene> amino acid distribution.<br />
<br />
<br />
The protein <scene name='82/829351/Parg/1'>PARG</scene> folds into an ADP-ribose-binding macro domain with an N-terminal extension. It also consists of a diphosphate-binding loop on one side of an ADP-ribose binding cavity. On the other side there are several amino acids matching to the specific PARG signature sequence. <br />
In the macro domain fold, a loop is inserted to welcome the Glu115 side chain protecting the active site of the PARG protein. This loop gives PARG the ability to hydrolyze PAR. The <scene name='82/829351/Parg_active_site/1'>hydrolysis of PAR happens in PARG catalytic domain</scene>. (PAR is represented here in pink).<br />
<br />
=== Post-translational modifications ===<br />
<br />
<br />
The protein is a complex composed of the [[ poly (ADP-ribose) glycohydrolase]] (PARG) and the anthraquinone PDD00013907. The Poly(ADP-ribose)glycohydrolase can interact with either [[PCNA]] or [[NUDT5]], this gives various possible functions to the protein. When this protein binds with NUDT5 it can remodel chromatin for example [http://www.uniprot.org/uniprot/Q86W56]. The post-translational modifications of the PAR protein (poly ADP-ribose) are important for DNA stability. <br />
PDD00013907 is, as already stated, an anthraquinone which is a polycyclic aromatic hydrocarbon usually used in biopesticides as a pest repellant. Here it is considered as a free <scene name='82/829351/7jb/1'>ligand</scene> (of identification number on PDB: 7JB) that can bind to the <scene name='82/829351/Parg/1'>PARG</scene> creating the<scene name='82/829351/Complex/1'> protein complex 6HMM</scene>. <br />
<br />
There are several possible post-translational modifications to stabilize DNA. Most commonly there would be phosphorylation, acetylation or methylation <ref>PMID: 21037856</ref>. Another post-translational modification concerning the 6HMM protein is made on the poly(ADP-ribose) protein (PAR). PAR is composed of a repetition of ADP-ribose units linked through glycosidic ribose-ribose bonds <ref>doi: 10.1038/nature10404</ref>. This allows the repair of single-strand breaks on DNA <ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792.">DOI: 10.1021/acs.jmedchem.8b01407</ref>. PARG, a constituent of the 6HMM protein, will degrade PAR to allow the <scene name='82/829351/Parp1_on_dna/1'>poly (ADP-ribose) polymerase (PARP)</scene> to free itself from the damaged site, that is now repaired, and completes as such reparation <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12.">PMID: 27689388</ref>.<br />
<br />
The anthraquinone PDD00013907 is a weakly active and cytotoxic anthraquinone 8a acting as a free ligand binding in the ADP-ribose binding site of the PARG. This PDD00013907 should lead to the inhibition of PARG, which is of interest in the search of novel cancer therapies <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. <br />
<br />
=== The mechanism ===<br />
As said previously, poly(ADP-ribosylation) is an important post-translational modification for DNA repair. The mechanism behind this repair relies on several factors. At first, the Poly (ADP-ribose) polymerase (PARP), more specifically the subtype [http://www.uniprot.org/uniprot/P09874 PARP1], will recognize and will bind to the single-stranded break on the DNA. It will then autophosphorylate due to NAD+ and form PAR chains. These will recruit other repair proteins to the site. <br />
<br />
The role of PARG is the hydrolyzation of the specific ribose-ribose bonds present in PAR which leads to its degradation and as such the reparation cycle will be finished<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/>. This degradation is important because without PARG the repair cycle cannot be completed <ref>PMID: 17548475</ref> and may lead to cell death. This is partially due to the still present PARP on the previously damaged site maintained by the non-degraded PAR <ref>PMID: 16140981</ref>. <br />
<br />
== Diseases and Relevance ==<br />
Due to the function of the protein poly (ADP-ribose) glycohydrolase PARG to be part of post-translational processes of DNA damage repair it could be used for new treatments in cancer therapy or for ther diseases. In cancer cells the rate of DNA damage is most probably higher than in normal cells. This could result from the considerably raised stress levels. A deficiency of PARG results in the cessing of the cell cycle and the following cell death<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/><ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. Consequently, the inhibition of PARG might be a solution on how to destroy tumor cells, for example.<br />
<br />
For the PAR protein, there has already been a lot of research concerning novel treatments, but not for PARG. As there are no close homologues of PARG<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/>, this protein provides a potential target in drug discovery.<br />
<br />
As the protein in complex with the anthraquinone does not work properly anymore [http://www.rcsb.org/structure/6HMM], the described complex shows how an inhibited PARG might act in the cell. The goal of searched therapeutics is therefore to find a way to get the protein PARG into a complex that is acting similar to the 6HMM complex. For now, the research for anthraquinone as inhibitor has stopped as it is cytotoxic for the cell<ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>.<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Laurine Grimandihttps://proteopedia.org/index.php?title=Sandbox_Reserved_1098&diff=3500176Sandbox Reserved 10982022-01-11T21:07:41Z<p>Laurine Grimandi: </p>
<hr />
<div>{{Sandbox_ESBS_2019}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==6HMM== <br />
<StructureSection load='6hmm' size='340' side='right' caption='[[6hmm]]' scene=''><br />
The <scene name='82/829351/6hmm/2'>6HMM protein</scene> is a human[[ poly (ADP-ribose) glycohydrolase]].It is the major enzyme responsible for the catabolism of poly (ADP-ribose), a reversible covalent-modifier of chromosomal proteins. The protein is found in many tissues and may be subject to proteolysis generating smaller, active products.<br />
This protein is only present when the DNA is damaged. It influences the damaged chromatin through a derepression of a gene promoter. Consequently this protein is quite interesting for biotechnological applications. Indeed, knowing the different pathways and protein interactions leading to DNA damage repair is a meaningful goal in research especially in new cancer therapies. <br />
<br />
<br />
=== catabolism of poly (ADP-ribose) ===<br />
<br />
This protein has four principal domains on a <scene name='82/829351/Single_chain/1'>single peptide chain</scene>: an A-domain, a catalytic domain and two substrate binding domains[http://www.uniprot.org/uniprot/Q86W56]. <br />
The first 456 amino acids of the peptide chain form the <scene name='82/829351/A_domain/1'>A-domain</scene>. Then, from the 610th to the 795th amino acids the <scene name='82/829351/Catalytic_domain/1'>catalytic domain</scene> can be found. This catalytic domain can bind to other proteins with <scene name='82/829351/Substrat_-_catalytic_domain/1'>two amino acids</scene> (the 726th and 727th amino acids). Next, <scene name='82/829351/Subtrat_jonction_domain_2/1'>the second substrate binding domain</scene> is located from the 869th to the 874th amino acid. [http://www.uniprot.org/uniprot/Q86W56]<br />
As such, most of the amino acids form the A-domain and the catalytic domain and only a few amino acids (8 a.a) make links with other proteins. Moreover, the ligand 7JB can bind the protein on the <scene name='82/829351/Liason_7jb/1'>754, 758, 792 and 795 amino acids</scene>. These amino acids are located on a helix and on a beta sheet. [http://www.rcsb.org/pdb/explore/remediatedSequence.do?structureId=6HMM]. There is the <scene name='82/829351/Distritbution_domain/1'>following</scene> amino acid distribution.<br />
<br />
<br />
The protein <scene name='82/829351/Parg/1'>PARG</scene> folds into an ADP-ribose-binding macro domain with an N-terminal extension. It also consists of a diphosphate-binding loop on one side of an ADP-ribose binding cavity. On the other side there are several amino acids matching to the specific PARG signature sequence. <br />
In the macro domain fold, a loop is inserted to welcome the Glu115 side chain protecting the active site of the PARG protein. This loop gives PARG the ability to hydrolyze PAR. The <scene name='82/829351/Parg_active_site/1'>hydrolysis of PAR happens in PARG catalytic domain</scene>. (PAR is represented here in pink).<br />
<br />
=== Post-translational modifications ===<br />
<br />
<br />
The protein is a complex composed of the [[ poly (ADP-ribose) glycohydrolase]] (PARG) and the anthraquinone PDD00013907. The Poly(ADP-ribose)glycohydrolase can interact with either [[PCNA]] or [[NUDT5]], this gives various possible functions to the protein. When this protein binds with NUDT5 it can remodel chromatin for example [http://www.uniprot.org/uniprot/Q86W56]. The post-translational modifications of the PAR protein (poly ADP-ribose) are important for DNA stability. <br />
PDD00013907 is, as already stated, an anthraquinone which is a polycyclic aromatic hydrocarbon usually used in biopesticides as a pest repellant. Here it is considered as a free <scene name='82/829351/7jb/1'>ligand</scene> (of identification number on PDB: 7JB) that can bind to the <scene name='82/829351/Parg/1'>PARG</scene> creating the<scene name='82/829351/Complex/1'> protein complex 6HMM</scene>. <br />
<br />
There are several possible post-translational modifications to stabilize DNA. Most commonly there would be phosphorylation, acetylation or methylation <ref>PMID: 21037856</ref>. Another post-translational modification concerning the 6HMM protein is made on the poly(ADP-ribose) protein (PAR). PAR is composed of a repetition of ADP-ribose units linked through glycosidic ribose-ribose bonds <ref>doi: 10.1038/nature10404</ref>. This allows the repair of single-strand breaks on DNA <ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792.">DOI: 10.1021/acs.jmedchem.8b01407</ref>. PARG, a constituent of the 6HMM protein, will degrade PAR to allow the <scene name='82/829351/Parp1_on_dna/1'>poly (ADP-ribose) polymerase (PARP)</scene> to free itself from the damaged site, that is now repaired, and completes as such reparation <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12.">PMID: 27689388</ref>.<br />
<br />
The anthraquinone PDD00013907 is a weakly active and cytotoxic anthraquinone 8a acting as a free ligand binding in the ADP-ribose binding site of the PARG. This PDD00013907 should lead to the inhibition of PARG, which is of interest in the search of novel cancer therapies <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. <br />
<br />
=== The mechanism ===<br />
As said previously, poly(ADP-ribosylation) is an important post-translational modification for DNA repair. The mechanism behind this repair relies on several factors. At first, the Poly (ADP-ribose) polymerase (PARP), more specifically the subtype [http://www.uniprot.org/uniprot/P09874 PARP1], will recognize and will bind to the single-stranded break on the DNA. It will then autophosphorylate due to NAD+ and form PAR chains. These will recruit other repair proteins to the site. <br />
<br />
The role of PARG is the hydrolyzation of the specific ribose-ribose bonds present in PAR which leads to its degradation and as such the reparation cycle will be finished<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/>. This degradation is important because without PARG the repair cycle cannot be completed <ref>PMID: 17548475</ref> and may lead to cell death. This is partially due to the still present PARP on the previously damaged site maintained by the non-degraded PAR <ref>PMID: 16140981</ref>. <br />
<br />
== Diseases and Relevance ==<br />
Due to the function of the protein poly (ADP-ribose) glycohydrolase PARG to be part of post-translational processes of DNA damage repair it could be used for new treatments in cancer therapy or for ther diseases. In cancer cells the rate of DNA damage is most probably higher than in normal cells. This could result from the considerably raised stress levels. A deficiency of PARG results in the cessing of the cell cycle and the following cell death<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/><ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. Consequently, the inhibition of PARG might be a solution on how to destroy tumor cells, for example.<br />
<br />
For the PAR protein, there has already been a lot of research concerning novel treatments, but not for PARG. As there are no close homologues of PARG<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/>, this protein provides a potential target in drug discovery.<br />
<br />
As the protein in complex with the anthraquinone does not work properly anymore [http://www.rcsb.org/structure/6HMM], the described complex shows how an inhibited PARG might act in the cell. The goal of searched therapeutics is therefore to find a way to get the protein PARG into a complex that is acting similar to the 6HMM complex. For now, the research for anthraquinone as inhibitor has stopped as it is cytotoxic for the cell<ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>.<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Laurine Grimandihttps://proteopedia.org/index.php?title=Sandbox_Reserved_1098&diff=3500173Sandbox Reserved 10982022-01-11T20:57:46Z<p>Laurine Grimandi: </p>
<hr />
<div>{{Sandbox_ESBS_2019}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==6HMM== <br />
<StructureSection load='6hmm' size='340' side='right' caption='[[6hmm]]' scene=''><br />
The <scene name='82/829351/6hmm/2'>6HMM protein</scene> is a human[[ poly (ADP-ribose) glycohydrolase]].It is the major enzyme responsible for the catabolism of poly (ADP-ribose), a reversible covalent-modifier of chromosomal proteins. The protein is found in many tissues and may be subject to proteolysis generating smaller, active products.<br />
This protein is only present when the DNA is damaged. It influences the damaged chromatin through a derepression of a gene promoter. Consequently this protein is quite interesting for biotechnological applications. Indeed, knowing the different pathways and protein interactions leading to DNA damage repair is a meaningful goal in research especially in new cancer therapies. <br />
<br />
<br />
=== catabolism of poly (ADP-ribose) ===<br />
<br />
This protein has four principal domains on a <scene name='82/829351/Single_chain/1'>single peptide chain</scene>: an A-domain, a catalytic domain and two substrate binding domains[http://www.uniprot.org/uniprot/Q86W56]. <br />
The first 456 amino acids of the peptide chain form the <scene name='82/829351/A_domain/1'>A-domain</scene>. Then, from the 610th to the 795th amino acids the <scene name='82/829351/Catalytic_domain/1'>catalytic domain</scene> can be found. This catalytic domain can bind to other proteins with <scene name='82/829351/Substrat_-_catalytic_domain/1'>two amino acids</scene> (the 726th and 727th amino acids). Next, <scene name='82/829351/Subtrat_jonction_domain_2/1'>the second substrate binding domain</scene> is located from the 869th to the 874th amino acid. [http://www.uniprot.org/uniprot/Q86W56]<br />
As such, most of the amino acids form the A-domain and the catalytic domain and only a few amino acids (8 a.a) make links with other proteins. Moreover, the ligand 7JB can bind the protein on the <scene name='82/829351/Liason_7jb/1'>754, 758, 792 and 795 amino acids</scene>. These amino acids are located on a helix and on a beta sheet. [http://www.rcsb.org/pdb/explore/remediatedSequence.do?structureId=6HMM]. There is the <scene name='82/829351/Distritbution_domain/1'>following</scene> amino acid distribution.<br />
<br />
<br />
The protein <scene name='82/829351/Parg/1'>PARG</scene> folds into an ADP-ribose-binding macro domain with an N-terminal extension. It also consists of a diphosphate-binding loop on one side of an ADP-ribose binding cavity. On the other side there are several amino acids matching to the specific PARG signature sequence. <br />
In the macro domain fold, a loop is inserted to welcome the Glu115 side chain protecting the active site of the PARG protein. This loop gives PARG the ability to hydrolyze PAR. The <scene name='82/829351/Parg_active_site/1'>hydrolysis of PAR happens in PARG catalytic domain</scene>. (PAR is represented here in pink).<br />
<br />
=== Post-translational modifications ===<br />
<br />
<br />
The protein is a complex composed of the [[ poly (ADP-ribose) glycohydrolase]] (PARG) and the anthraquinone PDD00013907. The Poly(ADP-ribose)glycohydrolase can interact with either [[PCNA]] or [[NUDT5]], this gives various possible functions to the protein. When this protein binds with NUDT5 it can remodel chromatin for example [http://www.uniprot.org/uniprot/Q86W56]. The post-translational modifications of the PAR protein (poly ADP-ribose) are important for DNA stability. <br />
PDD00013907 is, as already stated, an anthraquinone which is a polycyclic aromatic hydrocarbon usually used in biopesticides as a pest repellant. Here it is considered as a free <scene name='82/829351/7jb/1'>ligand</scene> (of identification number on PDB: 7JB) that can bind to the <scene name='82/829351/Parg/1'>PARG</scene> creating the<scene name='82/829351/Complex/1'> protein complex 6HMM</scene>. <br />
<br />
There are several possible post-translational modifications to stabilize DNA. Most commonly there would be phosphorylation, acetylation or methylation <ref>PMID: 21037856</ref>. Another post-translational modification concerning the 6HMM protein is made on the poly(ADP-ribose) protein (PAR). PAR is composed of a repetition of ADP-ribose units linked through glycosidic ribose-ribose bonds <ref>doi: 10.1038/nature10404</ref>. This allows the repair of single-strand breaks on DNA <ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792.">DOI: 10.1021/acs.jmedchem.8b01407</ref>. PARG, a constituent of the 6HMM protein, will degrade PAR to allow the poly (ADP-ribose) polymerase (PARP) to free itself from the damaged site, that is now repaired, and completes as such reparation <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12.">PMID: 27689388</ref>.<br />
<br />
The anthraquinone PDD00013907 is a weakly active and cytotoxic anthraquinone 8a acting as a free ligand binding in the ADP-ribose binding site of the PARG. This PDD00013907 should lead to the inhibition of PARG, which is of interest in the search of novel cancer therapies <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. <br />
<br />
=== The mechanism ===<br />
As said previously, poly(ADP-ribosylation) is an important post-translational modification for DNA repair. The mechanism behind this repair relies on several factors. At first, the Poly (ADP-ribose) polymerase (PARP), more specifically the subtype [http://www.uniprot.org/uniprot/P09874 PARP1], will recognize and will bind to the single-stranded break on the DNA. It will then autophosphorylate due to NAD+ and form PAR chains. These will recruit other repair proteins to the site. <br />
<br />
The role of PARG is the hydrolyzation of the specific ribose-ribose bonds present in PAR which leads to its degradation and as such the reparation cycle will be finished<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/>. This degradation is important because without PARG the repair cycle cannot be completed <ref>PMID: 17548475</ref> and may lead to cell death. This is partially due to the still present PARP on the previously damaged site maintained by the non-degraded PAR <ref>PMID: 16140981</ref>. <br />
<br />
== Diseases and Relevance ==<br />
Due to the function of the protein poly (ADP-ribose) glycohydrolase PARG to be part of post-translational processes of DNA damage repair it could be used for new treatments in cancer therapy or for ther diseases. In cancer cells the rate of DNA damage is most probably higher than in normal cells. This could result from the considerably raised stress levels. A deficiency of PARG results in the cessing of the cell cycle and the following cell death<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/><ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. Consequently, the inhibition of PARG might be a solution on how to destroy tumor cells, for example.<br />
<br />
For the PAR protein, there has already been a lot of research concerning novel treatments, but not for PARG. As there are no close homologues of PARG<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/>, this protein provides a potential target in drug discovery.<br />
<br />
As the protein in complex with the anthraquinone does not work properly anymore [http://www.rcsb.org/structure/6HMM], the described complex shows how an inhibited PARG might act in the cell. The goal of searched therapeutics is therefore to find a way to get the protein PARG into a complex that is acting similar to the 6HMM complex. For now, the research for anthraquinone as inhibitor has stopped as it is cytotoxic for the cell<ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>.<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Laurine Grimandihttps://proteopedia.org/index.php?title=Sandbox_Reserved_1098&diff=3500171Sandbox Reserved 10982022-01-11T20:43:24Z<p>Laurine Grimandi: </p>
<hr />
<div>{{Sandbox_ESBS_2019}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==6HMM== <br />
<StructureSection load='6hmm' size='340' side='right' caption='[[6hmm]]' scene=''><br />
The <scene name='82/829351/6hmm/2'>6HMM protein</scene> is a human[[ poly (ADP-ribose) glycohydrolase]].It is the major enzyme responsible for the catabolism of poly (ADP-ribose), a reversible covalent-modifier of chromosomal proteins. The protein is found in many tissues and may be subject to proteolysis generating smaller, active products.<br />
This protein is only present when the DNA is damaged. It influences the damaged chromatin through a derepression of a gene promoter. Consequently this protein is quite interesting for biotechnological applications. Indeed, knowing the different pathways and protein interactions leading to DNA damage repair is a meaningful goal in research especially in new cancer therapies. <br />
<br />
<br />
=== catabolism of poly (ADP-ribose) ===<br />
<br />
This protein has four principal domains on a <scene name='82/829351/Single_chain/1'>single peptide chain</scene>: an A-domain, a catalytic domain and two substrate binding domains[http://www.uniprot.org/uniprot/Q86W56]. <br />
The first 456 amino acids of the peptide chain form the <scene name='82/829351/A_domain/1'>A-domain</scene>. Then, from the 610th to the 795th amino acids the <scene name='82/829351/Catalytic_domain/1'>catalytic domain</scene> can be found. This catalytic domain can bind to other proteins with <scene name='82/829351/Substrat_-_catalytic_domain/1'>two amino acids</scene> (the 726th and 727th amino acids). Next, <scene name='82/829351/Subtrat_jonction_domain_2/1'>the second substrate binding domain</scene> is located from the 869th to the 874th amino acid. [http://www.uniprot.org/uniprot/Q86W56]<br />
As such, most of the amino acids form the A-domain and the catalytic domain and only a few amino acids (8 a.a) make links with other proteins. Moreover, the ligand 7JB can bind the protein on the <scene name='82/829351/Liason_7jb/1'>754, 758, 792 and 795 amino acids</scene>. These amino acids are located on a helix and on a beta sheet. [http://www.rcsb.org/pdb/explore/remediatedSequence.do?structureId=6HMM]. There is the <scene name='82/829351/Distritbution_domain/1'>following</scene> amino acid distribution.<br />
<br />
<br />
The protein <scene name='82/829351/Parg/1'>PARG</scene> folds into an ADP-ribose-binding macro domain with an N-terminal extension. It also consists of a diphosphate-binding loop on one side of an ADP-ribose binding cavity. On the other side there are several amino acids matching to the specific PARG signature sequence. <br />
In the macro domain fold, a loop is inserted to welcome the Glu115 side chain protecting the active site of the PARG protein. This loop gives PARG the ability to hydrolyze PAR. The <scene name='82/829351/Parg_active_site/1'>hydrolysis of PAR happens in PARG catalytic domain</scene>. (PAR is represented here in pink).<br />
<br />
=== Post-translational modifications ===<br />
<br />
The Poly(ADP-ribose)glycohydrolase can interact with either [[PCNA]] or [[NUDT5]], this gives various possible functions to the protein. When this protein binds with NUDT5 it can remodel chromatin for example [http://www.uniprot.org/uniprot/Q86W56].<br />
<br />
The protein is a complex composed of the [[ poly (ADP-ribose) glycohydrolase]] (PARG) and the anthraquinone PDD00013907. The post-translational modifications of the PAR protein (poly ADP-ribose) are important for DNA stability. <br />
PDD00013907 is, as already stated, an anthraquinone which is a polycyclic aromatic hydrocarbon usually used in biopesticides as a pest repellant. Here it is considered as a free <scene name='82/829351/7jb/1'>ligand</scene> (of identification number on PDB: 7JB) that can bind to the <scene name='82/829351/Parg/1'>PARG</scene> creating the<scene name='82/829351/Complex/1'> protein complex 6HMM</scene>. <br />
<br />
There are several possible post-translational modifications to stabilize DNA. Most commonly there would be phosphorylation, acetylation or methylation <ref>PMID: 21037856</ref>. Another post-translational modification concerning the 6HMM protein is made on the poly(ADP-ribose) protein (PAR). PAR is composed of a repetition of ADP-ribose units linked through glycosidic ribose-ribose bonds <ref>doi: 10.1038/nature10404</ref>. This allows the repair of single-strand breaks on DNA <ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792.">DOI: 10.1021/acs.jmedchem.8b01407</ref>. PARG, a constituent of the 6HMM protein, will degrade PAR to allow the poly (ADP-ribose) polymerase (PARP) to free itself from the damaged site, that is now repaired, and completes as such reparation <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12.">PMID: 27689388</ref>.<br />
<br />
The anthraquinone PDD00013907 is a weakly active and cytotoxic anthraquinone 8a acting as a free ligand binding in the ADP-ribose binding site of the PARG. This PDD00013907 should lead to the inhibition of PARG, which is of interest in the search of novel cancer therapies <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. <br />
<br />
=== The mechanism ===<br />
As said previously, poly(ADP-ribosylation) is an important post-translational modification for DNA repair. The mechanism behind this repair relies on several factors. At first, the Poly (ADP-ribose) polymerase (PARP), more specifically the subtype [http://www.uniprot.org/uniprot/P09874 PARP1], will recognize and will bind to the single-stranded break on the DNA. It will then autophosphorylate due to NAD+ and form PAR chains. These will recruit other repair proteins to the site. <br />
<br />
The role of PARG is the hydrolyzation of the specific ribose-ribose bonds present in PAR which leads to its degradation and as such the reparation cycle will be finished<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/>. This degradation is important because without PARG the repair cycle cannot be completed <ref>PMID: 17548475</ref> and may lead to cell death. This is partially due to the still present PARP on the previously damaged site maintained by the non-degraded PAR <ref>PMID: 16140981</ref>. <br />
<br />
== Diseases and Relevance ==<br />
Due to the function of the protein poly (ADP-ribose) glycohydrolase PARG to be part of post-translational processes of DNA damage repair it could be used for new treatments in cancer therapy or for ther diseases. In cancer cells the rate of DNA damage is most probably higher than in normal cells. This could result from the considerably raised stress levels. A deficiency of PARG results in the cessing of the cell cycle and the following cell death<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/><ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. Consequently, the inhibition of PARG might be a solution on how to destroy tumor cells, for example.<br />
<br />
For the PAR protein, there has already been a lot of research concerning novel treatments, but not for PARG. As there are no close homologues of PARG<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/>, this protein provides a potential target in drug discovery.<br />
<br />
As the protein in complex with the anthraquinone does not work properly anymore [http://www.rcsb.org/structure/6HMM], the described complex shows how an inhibited PARG might act in the cell. The goal of searched therapeutics is therefore to find a way to get the protein PARG into a complex that is acting similar to the 6HMM complex. For now, the research for anthraquinone as inhibitor has stopped as it is cytotoxic for the cell<ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>.<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Laurine Grimandihttps://proteopedia.org/index.php?title=Sandbox_Reserved_1098&diff=3500170Sandbox Reserved 10982022-01-11T20:42:07Z<p>Laurine Grimandi: </p>
<hr />
<div>{{Sandbox_ESBS_2019}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==6HMM== <br />
<StructureSection load='6hmm' size='340' side='right' caption='[[6hmm]]' scene=''><br />
The <scene name='82/829351/6hmm/2'>6HMM protein</scene> is a human[[ poly (ADP-ribose) glycohydrolase]].It is the major enzyme responsible for the catabolism of poly (ADP-ribose), a reversible covalent-modifier of chromosomal proteins. The protein is found in many tissues and may be subject to proteolysis generating smaller, active products.<br />
This protein is only present when the DNA is damaged. It influences the damaged chromatin through a derepression of a gene promoter. Consequently this protein is quite interesting for biotechnological applications. Indeed, knowing the different pathways and protein interactions leading to DNA damage repair is a meaningful goal in research especially in new cancer therapies. <br />
<br />
<br />
=== catabolism of poly (ADP-ribose) ===<br />
<br />
This protein has four principal domains on a <scene name='82/829351/Single_chain/1'>single peptide chain</scene>: an A-domain, a catalytic domain and two substrate binding domains[http://www.uniprot.org/uniprot/Q86W56]. <br />
The first 456 amino acids of the peptide chain form the <scene name='82/829351/A_domain/1'>A-domain</scene>. Then, from the 610th to the 795th amino acids the <scene name='82/829351/Catalytic_domain/1'>catalytic domain</scene> can be found. This catalytic domain can bind to other proteins with <scene name='82/829351/Substrat_-_catalytic_domain/1'>two amino acids</scene> (the 726th and 727th amino acids). Next, <scene name='82/829351/Subtrat_jonction_domain_2/1'>the second substrate binding domain</scene> is located from the 869th to the 874th amino acid. [http://www.uniprot.org/uniprot/Q86W56]<br />
As such, most of the amino acids form the A-domain and the catalytic domain and only a few amino acids (8 a.a) make links with other proteins. Moreover, the ligand 7JB can bind the protein on the <scene name='82/829351/Liason_7jb/1'>754, 758, 792 and 795 amino acids</scene>. These amino acids are located on a helix and on a beta sheet. [http://www.rcsb.org/pdb/explore/remediatedSequence.do?structureId=6HMM]. There is the <scene name='82/829351/Distritbution_domain/1'>following</scene> amino acid distribution.<br />
<br />
<br />
The protein <scene name='82/829351/Parg/1'>PARG</scene> folds into an ADP-ribose-binding macro domain with an N-terminal extension. It also consists of a diphosphate-binding loop on one side of an ADP-ribose binding cavity. On the other side there are several amino acids matching to the specific PARG signature sequence. <br />
In the macro domain fold, a loop is inserted to welcome the Glu115 side chain protecting the active site of the PARG protein. This loop gives PARG the ability to hydrolyze PAR. The <scene name='82/829351/Parg_active_site/1'>hydrolysis of PAR happens in PARG catalytic domain</scene>. (PAR is represented here in pink).<br />
<br />
<br />
<br />
The Poly(ADP-ribose)glycohydrolase can interact with either [[PCNA]] or [[NUDT5]], this gives various possible functions to the protein. When this protein binds with NUDT5 it can remodel chromatin for example [http://www.uniprot.org/uniprot/Q86W56].<br />
<br />
The protein is a complex composed of the [[ poly (ADP-ribose) glycohydrolase]] (PARG) and the anthraquinone PDD00013907. The post-translational modifications of the PAR protein (poly ADP-ribose) are important for DNA stability. <br />
PDD00013907 is, as already stated, an anthraquinone which is a polycyclic aromatic hydrocarbon usually used in biopesticides as a pest repellant. Here it is considered as a free <scene name='82/829351/7jb/1'>ligand</scene> (of identification number on PDB: 7JB) that can bind to the <scene name='82/829351/Parg/1'>PARG</scene> creating the<scene name='82/829351/Complex/1'> protein complex 6HMM</scene>. <br />
=== Post-translational modifications and anthraquinone===<br />
There are several possible post-translational modifications to stabilize DNA. Most commonly there would be phosphorylation, acetylation or methylation <ref>PMID: 21037856</ref>. Another post-translational modification concerning the 6HMM protein is made on the poly(ADP-ribose) protein (PAR). PAR is composed of a repetition of ADP-ribose units linked through glycosidic ribose-ribose bonds <ref>doi: 10.1038/nature10404</ref>. This allows the repair of single-strand breaks on DNA <ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792.">DOI: 10.1021/acs.jmedchem.8b01407</ref>. PARG, a constituent of the 6HMM protein, will degrade PAR to allow the poly (ADP-ribose) polymerase (PARP) to free itself from the damaged site, that is now repaired, and completes as such reparation <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12.">PMID: 27689388</ref>.<br />
<br />
The anthraquinone PDD00013907 is a weakly active and cytotoxic anthraquinone 8a acting as a free ligand binding in the ADP-ribose binding site of the PARG. This PDD00013907 should lead to the inhibition of PARG, which is of interest in the search of novel cancer therapies <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. <br />
<br />
=== The mechanism ===<br />
As said previously, poly(ADP-ribosylation) is an important post-translational modification for DNA repair. The mechanism behind this repair relies on several factors. At first, the Poly (ADP-ribose) polymerase (PARP), more specifically the subtype [http://www.uniprot.org/uniprot/P09874 PARP1], will recognize and will bind to the single-stranded break on the DNA. It will then autophosphorylate due to NAD+ and form PAR chains. These will recruit other repair proteins to the site. <br />
<br />
The role of PARG is the hydrolyzation of the specific ribose-ribose bonds present in PAR which leads to its degradation and as such the reparation cycle will be finished<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/>. This degradation is important because without PARG the repair cycle cannot be completed <ref>PMID: 17548475</ref> and may lead to cell death. This is partially due to the still present PARP on the previously damaged site maintained by the non-degraded PAR <ref>PMID: 16140981</ref>. <br />
<br />
== Diseases and Relevance ==<br />
Due to the function of the protein poly (ADP-ribose) glycohydrolase PARG to be part of post-translational processes of DNA damage repair it could be used for new treatments in cancer therapy or for ther diseases. In cancer cells the rate of DNA damage is most probably higher than in normal cells. This could result from the considerably raised stress levels. A deficiency of PARG results in the cessing of the cell cycle and the following cell death<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/><ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. Consequently, the inhibition of PARG might be a solution on how to destroy tumor cells, for example.<br />
<br />
For the PAR protein, there has already been a lot of research concerning novel treatments, but not for PARG. As there are no close homologues of PARG<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/>, this protein provides a potential target in drug discovery.<br />
<br />
As the protein in complex with the anthraquinone does not work properly anymore [http://www.rcsb.org/structure/6HMM], the described complex shows how an inhibited PARG might act in the cell. The goal of searched therapeutics is therefore to find a way to get the protein PARG into a complex that is acting similar to the 6HMM complex. For now, the research for anthraquinone as inhibitor has stopped as it is cytotoxic for the cell<ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>.<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Laurine Grimandihttps://proteopedia.org/index.php?title=Sandbox_Reserved_1098&diff=3500169Sandbox Reserved 10982022-01-11T20:41:03Z<p>Laurine Grimandi: </p>
<hr />
<div>{{Sandbox_ESBS_2019}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==6HMM== <br />
<StructureSection load='6hmm' size='340' side='right' caption='[[6hmm]]' scene=''><br />
The <scene name='82/829351/6hmm/2'>6HMM protein</scene> is a human[[ poly (ADP-ribose) glycohydrolase]].It is the major enzyme responsible for the catabolism of poly (ADP-ribose), a reversible covalent-modifier of chromosomal proteins. The protein is found in many tissues and may be subject to proteolysis generating smaller, active products.<br />
This protein is only present when the DNA is damaged. It influences the damaged chromatin through a derepression of a gene promoter. Consequently this protein is quite interesting for biotechnological applications. Indeed, knowing the different pathways and protein interactions leading to DNA damage repair is a meaningful goal in research especially in new cancer therapies. <br />
<br />
<br />
=== catabolism of poly (ADP-ribose) ===<br />
<br />
This protein has four principal domains on a <scene name='82/829351/Single_chain/1'>single peptide chain</scene>: an A-domain, a catalytic domain and two substrate binding domains[http://www.uniprot.org/uniprot/Q86W56]. <br />
The first 456 amino acids of the peptide chain form the <scene name='82/829351/A_domain/1'>A-domain</scene>. Then, from the 610th to the 795th amino acids the <scene name='82/829351/Catalytic_domain/1'>catalytic domain</scene> can be found. This catalytic domain can bind to other proteins with <scene name='82/829351/Substrat_-_catalytic_domain/1'>two amino acids</scene> (the 726th and 727th amino acids). Next, <scene name='82/829351/Subtrat_jonction_domain_2/1'>the second substrate binding domain</scene> is located from the 869th to the 874th amino acid. [http://www.uniprot.org/uniprot/Q86W56]<br />
As such, most of the amino acids form the A-domain and the catalytic domain and only a few amino acids (8 a.a) make links with other proteins. Moreover, the ligand 7JB can bind the protein on the <scene name='82/829351/Liason_7jb/1'>754, 758, 792 and 795 amino acids</scene>. These amino acids are located on a helix and on a beta sheet. [http://www.rcsb.org/pdb/explore/remediatedSequence.do?structureId=6HMM]. There is the <scene name='82/829351/Distritbution_domain/1'>following</scene> amino acid distribution.<br />
<br />
<br />
The protein <scene name='82/829351/Parg/1'>PARG</scene> folds into an ADP-ribose-binding macro domain with an N-terminal extension. It also consists of a diphosphate-binding loop on one side of an ADP-ribose binding cavity. On the other side there are several amino acids matching to the specific PARG signature sequence. <br />
In the macro domain fold, a loop is inserted to welcome the Glu115 side chain protecting the active site of the PARG protein. This loop gives PARG the ability to hydrolyze PAR. The <scene name='82/829351/Parg_active_site/1'>hydrolysis of PAR happens in PARG catalytic domain</scene>. (PAR is represented here in pink).<br />
<br />
<br />
=== Quaternary Structure ===<br />
<br />
The Poly(ADP-ribose)glycohydrolase can interact with either [[PCNA]] or [[NUDT5]], this gives various possible functions to the protein. When this protein binds with NUDT5 it can remodel chromatin for example [http://www.uniprot.org/uniprot/Q86W56].<br />
<br />
== Function ==<br />
The protein is a complex composed of the [[ poly (ADP-ribose) glycohydrolase]] (PARG) and the anthraquinone PDD00013907. The post-translational modifications of the PAR protein (poly ADP-ribose) are important for DNA stability. <br />
PDD00013907 is, as already stated, an anthraquinone which is a polycyclic aromatic hydrocarbon usually used in biopesticides as a pest repellant. Here it is considered as a free <scene name='82/829351/7jb/1'>ligand</scene> (of identification number on PDB: 7JB) that can bind to the <scene name='82/829351/Parg/1'>PARG</scene> creating the<scene name='82/829351/Complex/1'> protein complex 6HMM</scene>. <br />
=== Post-translational modifications and anthraquinone===<br />
There are several possible post-translational modifications to stabilize DNA. Most commonly there would be phosphorylation, acetylation or methylation <ref>PMID: 21037856</ref>. Another post-translational modification concerning the 6HMM protein is made on the poly(ADP-ribose) protein (PAR). PAR is composed of a repetition of ADP-ribose units linked through glycosidic ribose-ribose bonds <ref>doi: 10.1038/nature10404</ref>. This allows the repair of single-strand breaks on DNA <ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792.">DOI: 10.1021/acs.jmedchem.8b01407</ref>. PARG, a constituent of the 6HMM protein, will degrade PAR to allow the poly (ADP-ribose) polymerase (PARP) to free itself from the damaged site, that is now repaired, and completes as such reparation <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12.">PMID: 27689388</ref>.<br />
<br />
The anthraquinone PDD00013907 is a weakly active and cytotoxic anthraquinone 8a acting as a free ligand binding in the ADP-ribose binding site of the PARG. This PDD00013907 should lead to the inhibition of PARG, which is of interest in the search of novel cancer therapies <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. <br />
<br />
=== The mechanism ===<br />
As said previously, poly(ADP-ribosylation) is an important post-translational modification for DNA repair. The mechanism behind this repair relies on several factors. At first, the Poly (ADP-ribose) polymerase (PARP), more specifically the subtype [http://www.uniprot.org/uniprot/P09874 PARP1], will recognize and will bind to the single-stranded break on the DNA. It will then autophosphorylate due to NAD+ and form PAR chains. These will recruit other repair proteins to the site. <br />
<br />
The role of PARG is the hydrolyzation of the specific ribose-ribose bonds present in PAR which leads to its degradation and as such the reparation cycle will be finished<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/>. This degradation is important because without PARG the repair cycle cannot be completed <ref>PMID: 17548475</ref> and may lead to cell death. This is partially due to the still present PARP on the previously damaged site maintained by the non-degraded PAR <ref>PMID: 16140981</ref>. <br />
<br />
== Diseases and Relevance ==<br />
Due to the function of the protein poly (ADP-ribose) glycohydrolase PARG to be part of post-translational processes of DNA damage repair it could be used for new treatments in cancer therapy or for ther diseases. In cancer cells the rate of DNA damage is most probably higher than in normal cells. This could result from the considerably raised stress levels. A deficiency of PARG results in the cessing of the cell cycle and the following cell death<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/><ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. Consequently, the inhibition of PARG might be a solution on how to destroy tumor cells, for example.<br />
<br />
For the PAR protein, there has already been a lot of research concerning novel treatments, but not for PARG. As there are no close homologues of PARG<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/>, this protein provides a potential target in drug discovery.<br />
<br />
As the protein in complex with the anthraquinone does not work properly anymore [http://www.rcsb.org/structure/6HMM], the described complex shows how an inhibited PARG might act in the cell. The goal of searched therapeutics is therefore to find a way to get the protein PARG into a complex that is acting similar to the 6HMM complex. For now, the research for anthraquinone as inhibitor has stopped as it is cytotoxic for the cell<ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>.<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Laurine Grimandihttps://proteopedia.org/index.php?title=Sandbox_Reserved_1098&diff=3500168Sandbox Reserved 10982022-01-11T20:40:17Z<p>Laurine Grimandi: </p>
<hr />
<div>{{Sandbox_ESBS_2019}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==6HMM== <br />
<StructureSection load='6hmm' size='340' side='right' caption='[[6hmm]]' scene=''><br />
The <scene name='82/829351/6hmm/2'>6HMM protein</scene> is a human[[ poly (ADP-ribose) glycohydrolase]].It is the major enzyme responsible for the catabolism of poly (ADP-ribose), a reversible covalent-modifier of chromosomal proteins. The protein is found in many tissues and may be subject to proteolysis generating smaller, active products.<br />
This protein is only present when the DNA is damaged. It influences the damaged chromatin through a derepression of a gene promoter. Consequently this protein is quite interesting for biotechnological applications. Indeed, knowing the different pathways and protein interactions leading to DNA damage repair is a meaningful goal in research especially in new cancer therapies. <br />
<br />
<br />
=== catabolism of poly (ADP-ribose) ===<br />
<br />
This protein has four principal domains on a <scene name='82/829351/Single_chain/1'>single peptide chain</scene>: an A-domain, a catalytic domain and two substrate binding domains[http://www.uniprot.org/uniprot/Q86W56]. <br />
The first 456 amino acids of the peptide chain form the <scene name='82/829351/A_domain/1'>A-domain</scene>. Then, from the 610th to the 795th amino acids the <scene name='82/829351/Catalytic_domain/1'>catalytic domain</scene> can be found. This catalytic domain can bind to other proteins with <scene name='82/829351/Substrat_-_catalytic_domain/1'>two amino acids</scene> (the 726th and 727th amino acids). Next, <scene name='82/829351/Subtrat_jonction_domain_2/1'>the second substrate binding domain</scene> is located from the 869th to the 874th amino acid. [http://www.uniprot.org/uniprot/Q86W56]<br />
As such, most of the amino acids form the A-domain and the catalytic domain and only a few amino acids (8 a.a) make links with other proteins. Moreover, the ligand 7JB can bind the protein on the <scene name='82/829351/Liason_7jb/1'>754, 758, 792 and 795 amino acids</scene>. These amino acids are located on a helix and on a beta sheet. [http://www.rcsb.org/pdb/explore/remediatedSequence.do?structureId=6HMM]. There is the <scene name='82/829351/Distritbution_domain/1'>following</scene> amino acid distribution.<br />
<br />
<br />
The protein <scene name='82/829351/Parg/1'>PARG</scene> folds into an ADP-ribose-binding macro domain with an N-terminal extension. It also consists of a diphosphate-binding loop on one side of an ADP-ribose binding cavity. On the other side there are several amino acids matching to the specific PARG signature sequence. <br />
In the macro domain fold, a loop is inserted to welcome the Glu115 side chain protecting the active site of the PARG protein. This loop gives PARG the ability to hydrolyze PAR. The <scene name='82/829351/Parg_active_site/1'>hydrolysis of PAR happens in PARG catalytic domain</scene>. (PAR is represented here in pink).<br />
Concerning the ligand pairing with the PARG protein only a small difference can be observed for the amino acids Val226 and Phe227 <ref>PMID: 21892188</ref>.<br />
<br />
=== Quaternary Structure ===<br />
<br />
The Poly(ADP-ribose)glycohydrolase can interact with either [[PCNA]] or [[NUDT5]], this gives various possible functions to the protein. When this protein binds with NUDT5 it can remodel chromatin for example [http://www.uniprot.org/uniprot/Q86W56].<br />
<br />
== Function ==<br />
The protein is a complex composed of the [[ poly (ADP-ribose) glycohydrolase]] (PARG) and the anthraquinone PDD00013907. The post-translational modifications of the PAR protein (poly ADP-ribose) are important for DNA stability. <br />
PDD00013907 is, as already stated, an anthraquinone which is a polycyclic aromatic hydrocarbon usually used in biopesticides as a pest repellant. Here it is considered as a free <scene name='82/829351/7jb/1'>ligand</scene> (of identification number on PDB: 7JB) that can bind to the <scene name='82/829351/Parg/1'>PARG</scene> creating the<scene name='82/829351/Complex/1'> protein complex 6HMM</scene>. <br />
=== Post-translational modifications and anthraquinone===<br />
There are several possible post-translational modifications to stabilize DNA. Most commonly there would be phosphorylation, acetylation or methylation <ref>PMID: 21037856</ref>. Another post-translational modification concerning the 6HMM protein is made on the poly(ADP-ribose) protein (PAR). PAR is composed of a repetition of ADP-ribose units linked through glycosidic ribose-ribose bonds <ref>doi: 10.1038/nature10404</ref>. This allows the repair of single-strand breaks on DNA <ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792.">DOI: 10.1021/acs.jmedchem.8b01407</ref>. PARG, a constituent of the 6HMM protein, will degrade PAR to allow the poly (ADP-ribose) polymerase (PARP) to free itself from the damaged site, that is now repaired, and completes as such reparation <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12.">PMID: 27689388</ref>.<br />
<br />
The anthraquinone PDD00013907 is a weakly active and cytotoxic anthraquinone 8a acting as a free ligand binding in the ADP-ribose binding site of the PARG. This PDD00013907 should lead to the inhibition of PARG, which is of interest in the search of novel cancer therapies <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. <br />
<br />
=== The mechanism ===<br />
As said previously, poly(ADP-ribosylation) is an important post-translational modification for DNA repair. The mechanism behind this repair relies on several factors. At first, the Poly (ADP-ribose) polymerase (PARP), more specifically the subtype [http://www.uniprot.org/uniprot/P09874 PARP1], will recognize and will bind to the single-stranded break on the DNA. It will then autophosphorylate due to NAD+ and form PAR chains. These will recruit other repair proteins to the site. <br />
<br />
The role of PARG is the hydrolyzation of the specific ribose-ribose bonds present in PAR which leads to its degradation and as such the reparation cycle will be finished<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/>. This degradation is important because without PARG the repair cycle cannot be completed <ref>PMID: 17548475</ref> and may lead to cell death. This is partially due to the still present PARP on the previously damaged site maintained by the non-degraded PAR <ref>PMID: 16140981</ref>. <br />
<br />
== Diseases and Relevance ==<br />
Due to the function of the protein poly (ADP-ribose) glycohydrolase PARG to be part of post-translational processes of DNA damage repair it could be used for new treatments in cancer therapy or for ther diseases. In cancer cells the rate of DNA damage is most probably higher than in normal cells. This could result from the considerably raised stress levels. A deficiency of PARG results in the cessing of the cell cycle and the following cell death<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/><ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. Consequently, the inhibition of PARG might be a solution on how to destroy tumor cells, for example.<br />
<br />
For the PAR protein, there has already been a lot of research concerning novel treatments, but not for PARG. As there are no close homologues of PARG<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/>, this protein provides a potential target in drug discovery.<br />
<br />
As the protein in complex with the anthraquinone does not work properly anymore [http://www.rcsb.org/structure/6HMM], the described complex shows how an inhibited PARG might act in the cell. The goal of searched therapeutics is therefore to find a way to get the protein PARG into a complex that is acting similar to the 6HMM complex. For now, the research for anthraquinone as inhibitor has stopped as it is cytotoxic for the cell<ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>.<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Laurine Grimandihttps://proteopedia.org/index.php?title=Sandbox_Reserved_1098&diff=3500164Sandbox Reserved 10982022-01-11T20:23:41Z<p>Laurine Grimandi: </p>
<hr />
<div>{{Sandbox_ESBS_2019}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==6HMM== <br />
<StructureSection load='6hmm' size='340' side='right' caption='[[6hmm]]' scene=''><br />
The <scene name='82/829351/6hmm/2'>6HMM protein</scene> is a human[[ poly (ADP-ribose) glycohydrolase]].It is the major enzyme responsible for the catabolism of poly (ADP-ribose), a reversible covalent-modifier of chromosomal proteins. The protein is found in many tissues and may be subject to proteolysis generating smaller, active products.<br />
This protein is only present when the DNA is damaged. It influences the damaged chromatin through a derepression of a gene promoter. Consequently this protein is quite interesting for biotechnological applications. Indeed, knowing the different pathways and protein interactions leading to DNA damage repair is a meaningful goal in research especially in new cancer therapies. <br />
<br />
<br />
=== catabolism of poly (ADP-ribose) ===<br />
<br />
This protein has four principal domains on a <scene name='82/829351/Single_chain/1'>single peptide chain</scene>: an A-domain, a catalytic domain and two substrate binding domains[http://www.uniprot.org/uniprot/Q86W56]. <br />
The first 456 amino acids of the peptide chain form the <scene name='82/829351/A_domain/1'>A-domain</scene>. Then, from the 610th to the 795th amino acids the <scene name='82/829351/Catalytic_domain/1'>catalytic domain</scene> can be found. This catalytic domain can bind to other proteins with <scene name='82/829351/Substrat_-_catalytic_domain/1'>two amino acids</scene> (the 726th and 727th amino acids). Next, <scene name='82/829351/Subtrat_jonction_domain_2/1'>the second substrate binding domain</scene> is located from the 869th to the 874th amino acid. [http://www.uniprot.org/uniprot/Q86W56]<br />
As such, most of the amino acids form the A-domain and the catalytic domain and only a few amino acids (8 a.a) make links with other proteins. Moreover, the ligand 7JB can bind the protein on the <scene name='82/829351/Liason_7jb/1'>754, 758, 792 and 795 amino acids</scene>. These amino acids are located on a helix and on a beta sheet. [http://www.rcsb.org/pdb/explore/remediatedSequence.do?structureId=6HMM]. There is the <scene name='82/829351/Distritbution_domain/1'>following</scene> amino acid distribution.<br />
<br />
<br />
The protein <scene name='82/829351/Parg/1'>PARG</scene> folds into an ADP-ribose-binding macro domain with an N-terminal extension. It also consists of a diphosphate-binding loop on one side of an ADP-ribose binding cavity. On the other side there are several amino acids matching to the specific PARG signature sequence. <br />
In the macro domain fold, a loop is inserted to welcome the Glu115 side chain protecting the active site of the PARG protein. This loop gives PARG the ability to hydrolyze PAR.<br />
Concerning the ligand pairing with the PARG protein only a small difference can be observed for the amino acids Val226 and Phe227 <ref>PMID: 21892188</ref>.<br />
<br />
=== Quaternary Structure ===<br />
<br />
The Poly(ADP-ribose)glycohydrolase can interact with either [[PCNA]] or [[NUDT5]], this gives various possible functions to the protein. When this protein binds with NUDT5 it can remodel chromatin for example [http://www.uniprot.org/uniprot/Q86W56].<br />
<br />
== Function ==<br />
The protein is a complex composed of the [[ poly (ADP-ribose) glycohydrolase]] (PARG) and the anthraquinone PDD00013907. The post-translational modifications of the PAR protein (poly ADP-ribose) are important for DNA stability. <br />
PDD00013907 is, as already stated, an anthraquinone which is a polycyclic aromatic hydrocarbon usually used in biopesticides as a pest repellant. Here it is considered as a free <scene name='82/829351/7jb/1'>ligand</scene> (of identification number on PDB: 7JB) that can bind to the <scene name='82/829351/Parg/1'>PARG</scene> creating the<scene name='82/829351/Complex/1'> protein complex 6HMM</scene>. <br />
=== Post-translational modifications and anthraquinone===<br />
There are several possible post-translational modifications to stabilize DNA. Most commonly there would be phosphorylation, acetylation or methylation <ref>PMID: 21037856</ref>. Another post-translational modification concerning the 6HMM protein is made on the poly(ADP-ribose) protein (PAR). PAR is composed of a repetition of ADP-ribose units linked through glycosidic ribose-ribose bonds <ref>doi: 10.1038/nature10404</ref>. This allows the repair of single-strand breaks on DNA <ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792.">DOI: 10.1021/acs.jmedchem.8b01407</ref>. PARG, a constituent of the 6HMM protein, will degrade PAR to allow the poly (ADP-ribose) polymerase (PARP) to free itself from the damaged site, that is now repaired, and completes as such reparation <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12.">PMID: 27689388</ref>.<br />
<br />
The anthraquinone PDD00013907 is a weakly active and cytotoxic anthraquinone 8a acting as a free ligand binding in the ADP-ribose binding site of the PARG. This PDD00013907 should lead to the inhibition of PARG, which is of interest in the search of novel cancer therapies <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. <br />
<br />
=== The mechanism ===<br />
As said previously, poly(ADP-ribosylation) is an important post-translational modification for DNA repair. The mechanism behind this repair relies on several factors. At first, the Poly (ADP-ribose) polymerase (PARP), more specifically the subtype [http://www.uniprot.org/uniprot/P09874 PARP1], will recognize and will bind to the single-stranded break on the DNA. It will then autophosphorylate due to NAD+ and form PAR chains. These will recruit other repair proteins to the site. <br />
<br />
The role of PARG is the hydrolyzation of the specific ribose-ribose bonds present in PAR which leads to its degradation and as such the reparation cycle will be finished<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/>. This degradation is important because without PARG the repair cycle cannot be completed <ref>PMID: 17548475</ref> and may lead to cell death. This is partially due to the still present PARP on the previously damaged site maintained by the non-degraded PAR <ref>PMID: 16140981</ref>. <br />
<br />
== Diseases and Relevance ==<br />
Due to the function of the protein poly (ADP-ribose) glycohydrolase PARG to be part of post-translational processes of DNA damage repair it could be used for new treatments in cancer therapy or for ther diseases. In cancer cells the rate of DNA damage is most probably higher than in normal cells. This could result from the considerably raised stress levels. A deficiency of PARG results in the cessing of the cell cycle and the following cell death<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/><ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. Consequently, the inhibition of PARG might be a solution on how to destroy tumor cells, for example.<br />
<br />
For the PAR protein, there has already been a lot of research concerning novel treatments, but not for PARG. As there are no close homologues of PARG<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/>, this protein provides a potential target in drug discovery.<br />
<br />
As the protein in complex with the anthraquinone does not work properly anymore [http://www.rcsb.org/structure/6HMM], the described complex shows how an inhibited PARG might act in the cell. The goal of searched therapeutics is therefore to find a way to get the protein PARG into a complex that is acting similar to the 6HMM complex. For now, the research for anthraquinone as inhibitor has stopped as it is cytotoxic for the cell<ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>.<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Laurine Grimandihttps://proteopedia.org/index.php?title=Sandbox_Reserved_1098&diff=3500160Sandbox Reserved 10982022-01-11T20:20:07Z<p>Laurine Grimandi: </p>
<hr />
<div>{{Sandbox_ESBS_2019}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==6HMM== <br />
<StructureSection load='6hmm' size='340' side='right' caption='[[6hmm]]' scene=''><br />
The <scene name='82/829351/6hmm/2'>6HMM protein</scene> is a human[[ poly (ADP-ribose) glycohydrolase]].It is the major enzyme responsible for the catabolism of poly (ADP-ribose), a reversible covalent-modifier of chromosomal proteins. The protein is found in many tissues and may be subject to proteolysis generating smaller, active products.<br />
This protein is only present when the DNA is damaged. It influences the damaged chromatin through a derepression of a gene promoter. Consequently this protein is quite interesting for biotechnological applications. Indeed, knowing the different pathways and protein interactions leading to DNA damage repair is a meaningful goal in research especially in new cancer therapies. <br />
<br />
<br />
=== catabolism of poly (ADP-ribose) ===<br />
<br />
This protein has four principal domains on a <scene name='82/829351/Single_chain/1'>single peptide chain</scene>: an A-domain, a catalytic domain and two substrate binding domains[http://www.uniprot.org/uniprot/Q86W56]. <br />
The first 456 amino acids of the peptide chain form the <scene name='82/829351/A_domain/1'>A-domain</scene>. Then, from the 610th to the 795th amino acids the <scene name='82/829351/Catalytic_domain/1'>catalytic domain</scene> can be found. This catalytic domain can bind to other proteins with <scene name='82/829351/Substrat_-_catalytic_domain/1'>two amino acids</scene> (the 726th and 727th amino acids). Next, <scene name='82/829351/Subtrat_jonction_domain_2/1'>the second substrate binding domain</scene> is located from the 869th to the 874th amino acid. [http://www.uniprot.org/uniprot/Q86W56]<br />
As such, most of the amino acids form the A-domain and the catalytic domain and only a few amino acids (8 a.a) make links with other proteins. Moreover, the ligand 7JB can bind the protein on the <scene name='82/829351/Liason_7jb/1'>754, 758, 792 and 795 amino acids</scene>. These amino acids are located on a helix and on a beta sheet. [http://www.rcsb.org/pdb/explore/remediatedSequence.do?structureId=6HMM]. There is the <scene name='82/829351/Distritbution_domain/1'>following</scene> amino acid distribution.<br />
<br />
<br />
=== Tertiary Structure === <br />
<br />
The protein PARG folds into an ADP-ribose-binding macro domain with an N-terminal extension. It also consists of a diphosphate-binding loop on one side of an ADP-ribose binding cavity. On the other side there are several amino acids matching to the specific PARG signature sequence. <br />
In the macro domain fold, a loop is inserted to welcome the Glu115 side chain protecting the active site of the PARG protein. This loop gives PARG the ability to hydrolyze PAR.<br />
Concerning the ligand pairing with the PARG protein only a small difference can be observed for the amino acids Val226 and Phe227 <ref>PMID: 21892188</ref>.<br />
<br />
=== Quaternary Structure ===<br />
<br />
The Poly(ADP-ribose)glycohydrolase can interact with either [[PCNA]] or [[NUDT5]], this gives various possible functions to the protein. When this protein binds with NUDT5 it can remodel chromatin for example [http://www.uniprot.org/uniprot/Q86W56].<br />
<br />
== Function ==<br />
The protein is a complex composed of the [[ poly (ADP-ribose) glycohydrolase]] (PARG) and the anthraquinone PDD00013907. The post-translational modifications of the PAR protein (poly ADP-ribose) are important for DNA stability. <br />
PDD00013907 is, as already stated, an anthraquinone which is a polycyclic aromatic hydrocarbon usually used in biopesticides as a pest repellant. Here it is considered as a free <scene name='82/829351/7jb/1'>ligand</scene> (of identification number on PDB: 7JB) that can bind to the <scene name='82/829351/Parg/1'>PARG</scene> creating the<scene name='82/829351/Complex/1'> protein complex 6HMM</scene>. <br />
=== Post-translational modifications and anthraquinone===<br />
There are several possible post-translational modifications to stabilize DNA. Most commonly there would be phosphorylation, acetylation or methylation <ref>PMID: 21037856</ref>. Another post-translational modification concerning the 6HMM protein is made on the poly(ADP-ribose) protein (PAR). PAR is composed of a repetition of ADP-ribose units linked through glycosidic ribose-ribose bonds <ref>doi: 10.1038/nature10404</ref>. This allows the repair of single-strand breaks on DNA <ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792.">DOI: 10.1021/acs.jmedchem.8b01407</ref>. PARG, a constituent of the 6HMM protein, will degrade PAR to allow the poly (ADP-ribose) polymerase (PARP) to free itself from the damaged site, that is now repaired, and completes as such reparation <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12.">PMID: 27689388</ref>.<br />
<br />
The anthraquinone PDD00013907 is a weakly active and cytotoxic anthraquinone 8a acting as a free ligand binding in the ADP-ribose binding site of the PARG. This PDD00013907 should lead to the inhibition of PARG, which is of interest in the search of novel cancer therapies <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. <br />
<br />
=== The mechanism ===<br />
As said previously, poly(ADP-ribosylation) is an important post-translational modification for DNA repair. The mechanism behind this repair relies on several factors. At first, the Poly (ADP-ribose) polymerase (PARP), more specifically the subtype [http://www.uniprot.org/uniprot/P09874 PARP1], will recognize and will bind to the single-stranded break on the DNA. It will then autophosphorylate due to NAD+ and form PAR chains. These will recruit other repair proteins to the site. <br />
<br />
The role of PARG is the hydrolyzation of the specific ribose-ribose bonds present in PAR which leads to its degradation and as such the reparation cycle will be finished<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/>. This degradation is important because without PARG the repair cycle cannot be completed <ref>PMID: 17548475</ref> and may lead to cell death. This is partially due to the still present PARP on the previously damaged site maintained by the non-degraded PAR <ref>PMID: 16140981</ref>. <br />
<br />
== Diseases and Relevance ==<br />
Due to the function of the protein poly (ADP-ribose) glycohydrolase PARG to be part of post-translational processes of DNA damage repair it could be used for new treatments in cancer therapy or for ther diseases. In cancer cells the rate of DNA damage is most probably higher than in normal cells. This could result from the considerably raised stress levels. A deficiency of PARG results in the cessing of the cell cycle and the following cell death<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/><ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. Consequently, the inhibition of PARG might be a solution on how to destroy tumor cells, for example.<br />
<br />
For the PAR protein, there has already been a lot of research concerning novel treatments, but not for PARG. As there are no close homologues of PARG<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/>, this protein provides a potential target in drug discovery.<br />
<br />
As the protein in complex with the anthraquinone does not work properly anymore [http://www.rcsb.org/structure/6HMM], the described complex shows how an inhibited PARG might act in the cell. The goal of searched therapeutics is therefore to find a way to get the protein PARG into a complex that is acting similar to the 6HMM complex. For now, the research for anthraquinone as inhibitor has stopped as it is cytotoxic for the cell<ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>.<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Laurine Grimandihttps://proteopedia.org/index.php?title=Sandbox_Reserved_1098&diff=3500159Sandbox Reserved 10982022-01-11T20:16:04Z<p>Laurine Grimandi: </p>
<hr />
<div>{{Sandbox_ESBS_2019}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==6HMM== <br />
<StructureSection load='6hmm' size='340' side='right' caption='[[6hmm]]' scene=''><br />
The <scene name='82/829351/6hmm/2'>6HMM protein</scene> is a human[[ poly (ADP-ribose) glycohydrolase]].It is the major enzyme responsible for the catabolism of poly (ADP-ribose), a reversible covalent-modifier of chromosomal proteins. The protein is found in many tissues and may be subject to proteolysis generating smaller, active products.<br />
This protein is only present when the DNA is damaged. It influences the damaged chromatin through a derepression of a gene promoter. Consequently this protein is quite interesting for biotechnological applications. Indeed, knowing the different pathways and protein interactions leading to DNA damage repair is a meaningful goal in research especially in new cancer therapies. <br />
<br />
<br />
=== catabolism of poly (ADP-ribose) ===<br />
<br />
This protein has four principal domains on a <scene name='82/829351/Single_chain/1'>single peptide chain</scene>: an A-domain, a catalytic domain and two substrate binding domains[http://www.uniprot.org/uniprot/Q86W56]. <br />
The first 456 amino acids of the peptide chain form the <scene name='82/829351/A_domain/1'>A-domain</scene>. Then, from the 610th to the 795th amino acids the <scene name='82/829351/Catalytic_domain/1'>catalytic domain</scene> can be found. This catalytic domain can bind to other proteins with <scene name='82/829351/Substrat_-_catalytic_domain/1'>two amino acids</scene> (the 726th and 727th amino acids). Next, <scene name='82/829351/Subtrat_jonction_domain_2/1'>the second substrate binding domain</scene> is located from the 869th to the 874th amino acid. [http://www.uniprot.org/uniprot/Q86W56]<br />
As such, most of the amino acids form the A-domain and the catalytic domain and only a few amino acids (8 a.a) make links with other proteins. Moreover, the ligand 7JB can bind the protein on the <scene name='82/829351/Liason_7jb/1'>754, 758, 792 and 795 amino acids</scene>. These amino acids are located on a helix and on a beta sheet. [http://www.rcsb.org/pdb/explore/remediatedSequence.do?structureId=6HMM]. There is the <scene name='82/829351/Distritbution_domain/1'>following</scene> amino acid distribution.<br />
<br />
=== Secondary Structure === <br />
<br />
This protein is 37% <scene name='82/829351/Helix/1'>helical</scene> and 13% <scene name='82/829351/Sheet/1'>beta sheet</scene>, distributed <scene name='82/829351/Helix_and_beta_sheet/1'>as such</scene>. Indeed, 6HMM has 25 helices on 198 residues and 23 strands on 74 residues. It also has a few 3/10 helices. [http://www.rcsb.org/pdb/explore/remediatedSequence.do?structureId=6HMM] <br />
Concerning the torsion angles, the backbone angles and the sidechain angles can be differentiated. Indeed, no residue in the <scene name='82/829351/Mainchain/1'>backbone</scene> does not respect the Ramachandran's angle, whereas only 2% of the residues on the sidechain are Ramachandran outliers due to having a non-rotameric form. [http://files.rcsb.org/pub/pdb/validation_reports/hm/6hmm/6hmm_full_validation.pdf]<br />
<br />
=== Tertiary Structure === <br />
<br />
The protein PARG folds into an ADP-ribose-binding macro domain with an N-terminal extension. It also consists of a diphosphate-binding loop on one side of an ADP-ribose binding cavity. On the other side there are several amino acids matching to the specific PARG signature sequence. <br />
In the macro domain fold, a loop is inserted to welcome the Glu115 side chain protecting the active site of the PARG protein. This loop gives PARG the ability to hydrolyze PAR.<br />
Concerning the ligand pairing with the PARG protein only a small difference can be observed for the amino acids Val226 and Phe227 <ref>PMID: 21892188</ref>.<br />
<br />
=== Quaternary Structure ===<br />
<br />
The Poly(ADP-ribose)glycohydrolase can interact with either [[PCNA]] or [[NUDT5]], this gives various possible functions to the protein. When this protein binds with NUDT5 it can remodel chromatin for example [http://www.uniprot.org/uniprot/Q86W56].<br />
<br />
== Function ==<br />
The protein is a complex composed of the [[ poly (ADP-ribose) glycohydrolase]] (PARG) and the anthraquinone PDD00013907. The post-translational modifications of the PAR protein (poly ADP-ribose) are important for DNA stability. <br />
PDD00013907 is, as already stated, an anthraquinone which is a polycyclic aromatic hydrocarbon usually used in biopesticides as a pest repellant. Here it is considered as a free <scene name='82/829351/7jb/1'>ligand</scene> (of identification number on PDB: 7JB) that can bind to the <scene name='82/829351/Parg/1'>PARG</scene> creating the<scene name='82/829351/Complex/1'> protein complex 6HMM</scene>. <br />
=== Post-translational modifications and anthraquinone===<br />
There are several possible post-translational modifications to stabilize DNA. Most commonly there would be phosphorylation, acetylation or methylation <ref>PMID: 21037856</ref>. Another post-translational modification concerning the 6HMM protein is made on the poly(ADP-ribose) protein (PAR). PAR is composed of a repetition of ADP-ribose units linked through glycosidic ribose-ribose bonds <ref>doi: 10.1038/nature10404</ref>. This allows the repair of single-strand breaks on DNA <ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792.">DOI: 10.1021/acs.jmedchem.8b01407</ref>. PARG, a constituent of the 6HMM protein, will degrade PAR to allow the poly (ADP-ribose) polymerase (PARP) to free itself from the damaged site, that is now repaired, and completes as such reparation <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12.">PMID: 27689388</ref>.<br />
<br />
The anthraquinone PDD00013907 is a weakly active and cytotoxic anthraquinone 8a acting as a free ligand binding in the ADP-ribose binding site of the PARG. This PDD00013907 should lead to the inhibition of PARG, which is of interest in the search of novel cancer therapies <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. <br />
<br />
=== The mechanism ===<br />
As said previously, poly(ADP-ribosylation) is an important post-translational modification for DNA repair. The mechanism behind this repair relies on several factors. At first, the Poly (ADP-ribose) polymerase (PARP), more specifically the subtype [http://www.uniprot.org/uniprot/P09874 PARP1], will recognize and will bind to the single-stranded break on the DNA. It will then autophosphorylate due to NAD+ and form PAR chains. These will recruit other repair proteins to the site. <br />
<br />
The role of PARG is the hydrolyzation of the specific ribose-ribose bonds present in PAR which leads to its degradation and as such the reparation cycle will be finished<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/>. This degradation is important because without PARG the repair cycle cannot be completed <ref>PMID: 17548475</ref> and may lead to cell death. This is partially due to the still present PARP on the previously damaged site maintained by the non-degraded PAR <ref>PMID: 16140981</ref>. <br />
<br />
== Diseases and Relevance ==<br />
Due to the function of the protein poly (ADP-ribose) glycohydrolase PARG to be part of post-translational processes of DNA damage repair it could be used for new treatments in cancer therapy or for ther diseases. In cancer cells the rate of DNA damage is most probably higher than in normal cells. This could result from the considerably raised stress levels. A deficiency of PARG results in the cessing of the cell cycle and the following cell death<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/><ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. Consequently, the inhibition of PARG might be a solution on how to destroy tumor cells, for example.<br />
<br />
For the PAR protein, there has already been a lot of research concerning novel treatments, but not for PARG. As there are no close homologues of PARG<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/>, this protein provides a potential target in drug discovery.<br />
<br />
As the protein in complex with the anthraquinone does not work properly anymore [http://www.rcsb.org/structure/6HMM], the described complex shows how an inhibited PARG might act in the cell. The goal of searched therapeutics is therefore to find a way to get the protein PARG into a complex that is acting similar to the 6HMM complex. For now, the research for anthraquinone as inhibitor has stopped as it is cytotoxic for the cell<ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>.<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Laurine Grimandihttps://proteopedia.org/index.php?title=Sandbox_Reserved_1098&diff=3500158Sandbox Reserved 10982022-01-11T20:15:15Z<p>Laurine Grimandi: </p>
<hr />
<div>{{Sandbox_ESBS_2019}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==6HMM== <br />
<StructureSection load='6hmm' size='340' side='right' caption='[[6hmm]]' scene=''><br />
The <scene name='82/829351/6hmm/2'>6HMM protein</scene> is a human[[ poly (ADP-ribose) glycohydrolase]].It is the major enzyme responsible for the catabolism of poly (ADP-ribose), a reversible covalent-modifier of chromosomal proteins. The protein is found in many tissues and may be subject to proteolysis generating smaller, active products.<br />
This protein is only present when the DNA is damaged. It influences the damaged chromatin through a derepression of a gene promoter. Consequently this protein is quite interesting for biotechnological applications. Indeed, knowing the different pathways and protein interactions leading to DNA damage repair is a meaningful goal in research especially in new cancer therapies. <br />
<br />
<br />
== Structure ==<br />
<br />
<br />
=== catabolism of poly (ADP-ribose) ===<br />
<br />
This protein has four principal domains on a <scene name='82/829351/Single_chain/1'>single peptide chain</scene>: an A-domain, a catalytic domain and two substrate binding domains[http://www.uniprot.org/uniprot/Q86W56]. <br />
The first 456 amino acids of the peptide chain form the <scene name='82/829351/A_domain/1'>A-domain</scene>. Then, from the 610th to the 795th amino acids the <scene name='82/829351/Catalytic_domain/1'>catalytic domain</scene> can be found. This catalytic domain can bind to other proteins with <scene name='82/829351/Substrat_-_catalytic_domain/1'>two amino acids</scene> (the 726th and 727th amino acids). Next, <scene name='82/829351/Subtrat_jonction_domain_2/1'>the second substrate binding domain</scene> is located from the 869th to the 874th amino acid. [http://www.uniprot.org/uniprot/Q86W56]<br />
As such, most of the amino acids form the A-domain and the catalytic domain and only a few amino acids (8 a.a) make links with other proteins. Moreover, the ligand 7JB can bind the protein on the <scene name='82/829351/Liason_7jb/1'>754, 758, 792 and 795 amino acids</scene>. These amino acids are located on a helix and on a beta sheet. [http://www.rcsb.org/pdb/explore/remediatedSequence.do?structureId=6HMM]. There is the <scene name='82/829351/Distritbution_domain/1'>following</scene> amino acid distribution.<br />
<br />
=== Secondary Structure === <br />
<br />
This protein is 37% <scene name='82/829351/Helix/1'>helical</scene> and 13% <scene name='82/829351/Sheet/1'>beta sheet</scene>, distributed <scene name='82/829351/Helix_and_beta_sheet/1'>as such</scene>. Indeed, 6HMM has 25 helices on 198 residues and 23 strands on 74 residues. It also has a few 3/10 helices. [http://www.rcsb.org/pdb/explore/remediatedSequence.do?structureId=6HMM] <br />
Concerning the torsion angles, the backbone angles and the sidechain angles can be differentiated. Indeed, no residue in the <scene name='82/829351/Mainchain/1'>backbone</scene> does not respect the Ramachandran's angle, whereas only 2% of the residues on the sidechain are Ramachandran outliers due to having a non-rotameric form. [http://files.rcsb.org/pub/pdb/validation_reports/hm/6hmm/6hmm_full_validation.pdf]<br />
<br />
=== Tertiary Structure === <br />
<br />
The protein PARG folds into an ADP-ribose-binding macro domain with an N-terminal extension. It also consists of a diphosphate-binding loop on one side of an ADP-ribose binding cavity. On the other side there are several amino acids matching to the specific PARG signature sequence. <br />
In the macro domain fold, a loop is inserted to welcome the Glu115 side chain protecting the active site of the PARG protein. This loop gives PARG the ability to hydrolyze PAR.<br />
Concerning the ligand pairing with the PARG protein only a small difference can be observed for the amino acids Val226 and Phe227 <ref>PMID: 21892188</ref>.<br />
<br />
=== Quaternary Structure ===<br />
<br />
The Poly(ADP-ribose)glycohydrolase can interact with either [[PCNA]] or [[NUDT5]], this gives various possible functions to the protein. When this protein binds with NUDT5 it can remodel chromatin for example [http://www.uniprot.org/uniprot/Q86W56].<br />
<br />
== Function ==<br />
The protein is a complex composed of the [[ poly (ADP-ribose) glycohydrolase]] (PARG) and the anthraquinone PDD00013907. The post-translational modifications of the PAR protein (poly ADP-ribose) are important for DNA stability. <br />
PDD00013907 is, as already stated, an anthraquinone which is a polycyclic aromatic hydrocarbon usually used in biopesticides as a pest repellant. Here it is considered as a free <scene name='82/829351/7jb/1'>ligand</scene> (of identification number on PDB: 7JB) that can bind to the <scene name='82/829351/Parg/1'>PARG</scene> creating the<scene name='82/829351/Complex/1'> protein complex 6HMM</scene>. <br />
=== Post-translational modifications and anthraquinone===<br />
There are several possible post-translational modifications to stabilize DNA. Most commonly there would be phosphorylation, acetylation or methylation <ref>PMID: 21037856</ref>. Another post-translational modification concerning the 6HMM protein is made on the poly(ADP-ribose) protein (PAR). PAR is composed of a repetition of ADP-ribose units linked through glycosidic ribose-ribose bonds <ref>doi: 10.1038/nature10404</ref>. This allows the repair of single-strand breaks on DNA <ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792.">DOI: 10.1021/acs.jmedchem.8b01407</ref>. PARG, a constituent of the 6HMM protein, will degrade PAR to allow the poly (ADP-ribose) polymerase (PARP) to free itself from the damaged site, that is now repaired, and completes as such reparation <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12.">PMID: 27689388</ref>.<br />
<br />
The anthraquinone PDD00013907 is a weakly active and cytotoxic anthraquinone 8a acting as a free ligand binding in the ADP-ribose binding site of the PARG. This PDD00013907 should lead to the inhibition of PARG, which is of interest in the search of novel cancer therapies <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. <br />
<br />
=== The mechanism ===<br />
As said previously, poly(ADP-ribosylation) is an important post-translational modification for DNA repair. The mechanism behind this repair relies on several factors. At first, the Poly (ADP-ribose) polymerase (PARP), more specifically the subtype [http://www.uniprot.org/uniprot/P09874 PARP1], will recognize and will bind to the single-stranded break on the DNA. It will then autophosphorylate due to NAD+ and form PAR chains. These will recruit other repair proteins to the site. <br />
<br />
The role of PARG is the hydrolyzation of the specific ribose-ribose bonds present in PAR which leads to its degradation and as such the reparation cycle will be finished<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/>. This degradation is important because without PARG the repair cycle cannot be completed <ref>PMID: 17548475</ref> and may lead to cell death. This is partially due to the still present PARP on the previously damaged site maintained by the non-degraded PAR <ref>PMID: 16140981</ref>. <br />
<br />
== Diseases and Relevance ==<br />
Due to the function of the protein poly (ADP-ribose) glycohydrolase PARG to be part of post-translational processes of DNA damage repair it could be used for new treatments in cancer therapy or for ther diseases. In cancer cells the rate of DNA damage is most probably higher than in normal cells. This could result from the considerably raised stress levels. A deficiency of PARG results in the cessing of the cell cycle and the following cell death<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/><ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. Consequently, the inhibition of PARG might be a solution on how to destroy tumor cells, for example.<br />
<br />
For the PAR protein, there has already been a lot of research concerning novel treatments, but not for PARG. As there are no close homologues of PARG<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/>, this protein provides a potential target in drug discovery.<br />
<br />
As the protein in complex with the anthraquinone does not work properly anymore [http://www.rcsb.org/structure/6HMM], the described complex shows how an inhibited PARG might act in the cell. The goal of searched therapeutics is therefore to find a way to get the protein PARG into a complex that is acting similar to the 6HMM complex. For now, the research for anthraquinone as inhibitor has stopped as it is cytotoxic for the cell<ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>.<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Laurine Grimandihttps://proteopedia.org/index.php?title=Sandbox_Reserved_1098&diff=3500156Sandbox Reserved 10982022-01-11T20:09:22Z<p>Laurine Grimandi: </p>
<hr />
<div>{{Sandbox_ESBS_2019}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==6HMM== <br />
<StructureSection load='6hmm' size='340' side='right' caption='[[6hmm]]' scene=''><br />
The <scene name='82/829351/6hmm/2'>6HMM protein</scene> is a human[[ poly (ADP-ribose) glycohydrolase]].It is the major enzyme responsible for the catabolism of poly (ADP-ribose), a reversible covalent-modifier of chromosomal proteins. The protein is found in many tissues and may be subject to proteolysis generating smaller, active products.<br />
This protein is only present when the DNA is damaged. It influences the damaged chromatin through a derepression of a gene promoter. Consequently this protein is quite interesting for biotechnological applications. Indeed, knowing the different pathways and protein interactions leading to DNA damage repair is a meaningful goal in research especially in new cancer therapies. <br />
<br />
<br />
== Structure ==<br />
<br />
<br />
=== Structural highlights ===<br />
<br />
This protein has four principal domains on a <scene name='82/829351/Single_chain/1'>single peptide chain</scene>: an A-domain, a catalytic domain and two substrate binding domains[http://www.uniprot.org/uniprot/Q86W56]. <br />
The first 456 amino acids of the peptide chain form the <scene name='82/829351/A_domain/1'>A-domain</scene>. Then, from the 610th to the 795th amino acids the <scene name='82/829351/Catalytic_domain/1'>catalytic domain</scene> can be found. This catalytic domain can bind to other proteins with <scene name='82/829351/Substrat_-_catalytic_domain/1'>two amino acids</scene> (the 726th and 727th amino acids). Next, <scene name='82/829351/Subtrat_jonction_domain_2/1'>the second substrate binding domain</scene> is located from the 869th to the 874th amino acid. [http://www.uniprot.org/uniprot/Q86W56]<br />
As such, most of the amino acids form the A-domain and the catalytic domain and only a few amino acids (8 a.a) make links with other proteins. Moreover, the ligand 7JB can bind the protein on the <scene name='82/829351/Liason_7jb/1'>754, 758, 792 and 795 amino acids</scene>. These amino acids are located on a helix and on a beta sheet. [http://www.rcsb.org/pdb/explore/remediatedSequence.do?structureId=6HMM]. There is the <scene name='82/829351/Distritbution_domain/1'>following</scene> amino acid distribution.<br />
<br />
=== Secondary Structure === <br />
<br />
This protein is 37% <scene name='82/829351/Helix/1'>helical</scene> and 13% <scene name='82/829351/Sheet/1'>beta sheet</scene>, distributed <scene name='82/829351/Helix_and_beta_sheet/1'>as such</scene>. Indeed, 6HMM has 25 helices on 198 residues and 23 strands on 74 residues. It also has a few 3/10 helices. [http://www.rcsb.org/pdb/explore/remediatedSequence.do?structureId=6HMM] <br />
Concerning the torsion angles, the backbone angles and the sidechain angles can be differentiated. Indeed, no residue in the <scene name='82/829351/Mainchain/1'>backbone</scene> does not respect the Ramachandran's angle, whereas only 2% of the residues on the sidechain are Ramachandran outliers due to having a non-rotameric form. [http://files.rcsb.org/pub/pdb/validation_reports/hm/6hmm/6hmm_full_validation.pdf]<br />
<br />
=== Tertiary Structure === <br />
<br />
The protein PARG folds into an ADP-ribose-binding macro domain with an N-terminal extension. It also consists of a diphosphate-binding loop on one side of an ADP-ribose binding cavity. On the other side there are several amino acids matching to the specific PARG signature sequence. <br />
In the macro domain fold, a loop is inserted to welcome the Glu115 side chain protecting the active site of the PARG protein. This loop gives PARG the ability to hydrolyze PAR.<br />
Concerning the ligand pairing with the PARG protein only a small difference can be observed for the amino acids Val226 and Phe227 <ref>PMID: 21892188</ref>.<br />
<br />
=== Quaternary Structure ===<br />
<br />
The Poly(ADP-ribose)glycohydrolase can interact with either [[PCNA]] or [[NUDT5]], this gives various possible functions to the protein. When this protein binds with NUDT5 it can remodel chromatin for example [http://www.uniprot.org/uniprot/Q86W56].<br />
<br />
== Function ==<br />
The protein is a complex composed of the [[ poly (ADP-ribose) glycohydrolase]] (PARG) and the anthraquinone PDD00013907. The post-translational modifications of the PAR protein (poly ADP-ribose) are important for DNA stability. <br />
PDD00013907 is, as already stated, an anthraquinone which is a polycyclic aromatic hydrocarbon usually used in biopesticides as a pest repellant. Here it is considered as a free <scene name='82/829351/7jb/1'>ligand</scene> (of identification number on PDB: 7JB) that can bind to the <scene name='82/829351/Parg/1'>PARG</scene> creating the<scene name='82/829351/Complex/1'> protein complex 6HMM</scene>. <br />
=== Post-translational modifications and anthraquinone===<br />
There are several possible post-translational modifications to stabilize DNA. Most commonly there would be phosphorylation, acetylation or methylation <ref>PMID: 21037856</ref>. Another post-translational modification concerning the 6HMM protein is made on the poly(ADP-ribose) protein (PAR). PAR is composed of a repetition of ADP-ribose units linked through glycosidic ribose-ribose bonds <ref>doi: 10.1038/nature10404</ref>. This allows the repair of single-strand breaks on DNA <ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792.">DOI: 10.1021/acs.jmedchem.8b01407</ref>. PARG, a constituent of the 6HMM protein, will degrade PAR to allow the poly (ADP-ribose) polymerase (PARP) to free itself from the damaged site, that is now repaired, and completes as such reparation <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12.">PMID: 27689388</ref>.<br />
<br />
The anthraquinone PDD00013907 is a weakly active and cytotoxic anthraquinone 8a acting as a free ligand binding in the ADP-ribose binding site of the PARG. This PDD00013907 should lead to the inhibition of PARG, which is of interest in the search of novel cancer therapies <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. <br />
<br />
=== The mechanism ===<br />
As said previously, poly(ADP-ribosylation) is an important post-translational modification for DNA repair. The mechanism behind this repair relies on several factors. At first, the Poly (ADP-ribose) polymerase (PARP), more specifically the subtype [http://www.uniprot.org/uniprot/P09874 PARP1], will recognize and will bind to the single-stranded break on the DNA. It will then autophosphorylate due to NAD+ and form PAR chains. These will recruit other repair proteins to the site. <br />
<br />
The role of PARG is the hydrolyzation of the specific ribose-ribose bonds present in PAR which leads to its degradation and as such the reparation cycle will be finished<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/>. This degradation is important because without PARG the repair cycle cannot be completed <ref>PMID: 17548475</ref> and may lead to cell death. This is partially due to the still present PARP on the previously damaged site maintained by the non-degraded PAR <ref>PMID: 16140981</ref>. <br />
<br />
== Diseases and Relevance ==<br />
Due to the function of the protein poly (ADP-ribose) glycohydrolase PARG to be part of post-translational processes of DNA damage repair it could be used for new treatments in cancer therapy or for ther diseases. In cancer cells the rate of DNA damage is most probably higher than in normal cells. This could result from the considerably raised stress levels. A deficiency of PARG results in the cessing of the cell cycle and the following cell death<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/><ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. Consequently, the inhibition of PARG might be a solution on how to destroy tumor cells, for example.<br />
<br />
For the PAR protein, there has already been a lot of research concerning novel treatments, but not for PARG. As there are no close homologues of PARG<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/>, this protein provides a potential target in drug discovery.<br />
<br />
As the protein in complex with the anthraquinone does not work properly anymore [http://www.rcsb.org/structure/6HMM], the described complex shows how an inhibited PARG might act in the cell. The goal of searched therapeutics is therefore to find a way to get the protein PARG into a complex that is acting similar to the 6HMM complex. For now, the research for anthraquinone as inhibitor has stopped as it is cytotoxic for the cell<ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>.<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Laurine Grimandihttps://proteopedia.org/index.php?title=Sandbox_Reserved_1098&diff=3500155Sandbox Reserved 10982022-01-11T20:08:53Z<p>Laurine Grimandi: </p>
<hr />
<div>{{Sandbox_ESBS_2019}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==6HMM== <br />
<StructureSection load='6hmm' size='340' side='right' caption='[[6hmm]]' scene=''><br />
The <scene name='82/829351/6hmm/2'>6HMM protein</scene> is a human[[ poly (ADP-ribose) glycohydrolase]]. <br />
is the major enzyme responsible for the catabolism of poly (ADP-ribose), a reversible covalent-modifier of chromosomal proteins. The protein is found in many tissues and may be subject to proteolysis generating smaller, active products.<br />
This protein is only present when the DNA is damaged. It influences the damaged chromatin through a derepression of a gene promoter. Consequently this protein is quite interesting for biotechnological applications. Indeed, knowing the different pathways and protein interactions leading to DNA damage repair is a meaningful goal in research especially in new cancer therapies. <br />
<br />
<br />
== Structure ==<br />
<br />
<br />
=== Structural highlights ===<br />
<br />
This protein has four principal domains on a <scene name='82/829351/Single_chain/1'>single peptide chain</scene>: an A-domain, a catalytic domain and two substrate binding domains[http://www.uniprot.org/uniprot/Q86W56]. <br />
The first 456 amino acids of the peptide chain form the <scene name='82/829351/A_domain/1'>A-domain</scene>. Then, from the 610th to the 795th amino acids the <scene name='82/829351/Catalytic_domain/1'>catalytic domain</scene> can be found. This catalytic domain can bind to other proteins with <scene name='82/829351/Substrat_-_catalytic_domain/1'>two amino acids</scene> (the 726th and 727th amino acids). Next, <scene name='82/829351/Subtrat_jonction_domain_2/1'>the second substrate binding domain</scene> is located from the 869th to the 874th amino acid. [http://www.uniprot.org/uniprot/Q86W56]<br />
As such, most of the amino acids form the A-domain and the catalytic domain and only a few amino acids (8 a.a) make links with other proteins. Moreover, the ligand 7JB can bind the protein on the <scene name='82/829351/Liason_7jb/1'>754, 758, 792 and 795 amino acids</scene>. These amino acids are located on a helix and on a beta sheet. [http://www.rcsb.org/pdb/explore/remediatedSequence.do?structureId=6HMM]. There is the <scene name='82/829351/Distritbution_domain/1'>following</scene> amino acid distribution.<br />
<br />
=== Secondary Structure === <br />
<br />
This protein is 37% <scene name='82/829351/Helix/1'>helical</scene> and 13% <scene name='82/829351/Sheet/1'>beta sheet</scene>, distributed <scene name='82/829351/Helix_and_beta_sheet/1'>as such</scene>. Indeed, 6HMM has 25 helices on 198 residues and 23 strands on 74 residues. It also has a few 3/10 helices. [http://www.rcsb.org/pdb/explore/remediatedSequence.do?structureId=6HMM] <br />
Concerning the torsion angles, the backbone angles and the sidechain angles can be differentiated. Indeed, no residue in the <scene name='82/829351/Mainchain/1'>backbone</scene> does not respect the Ramachandran's angle, whereas only 2% of the residues on the sidechain are Ramachandran outliers due to having a non-rotameric form. [http://files.rcsb.org/pub/pdb/validation_reports/hm/6hmm/6hmm_full_validation.pdf]<br />
<br />
=== Tertiary Structure === <br />
<br />
The protein PARG folds into an ADP-ribose-binding macro domain with an N-terminal extension. It also consists of a diphosphate-binding loop on one side of an ADP-ribose binding cavity. On the other side there are several amino acids matching to the specific PARG signature sequence. <br />
In the macro domain fold, a loop is inserted to welcome the Glu115 side chain protecting the active site of the PARG protein. This loop gives PARG the ability to hydrolyze PAR.<br />
Concerning the ligand pairing with the PARG protein only a small difference can be observed for the amino acids Val226 and Phe227 <ref>PMID: 21892188</ref>.<br />
<br />
=== Quaternary Structure ===<br />
<br />
The Poly(ADP-ribose)glycohydrolase can interact with either [[PCNA]] or [[NUDT5]], this gives various possible functions to the protein. When this protein binds with NUDT5 it can remodel chromatin for example [http://www.uniprot.org/uniprot/Q86W56].<br />
<br />
== Function ==<br />
The protein is a complex composed of the [[ poly (ADP-ribose) glycohydrolase]] (PARG) and the anthraquinone PDD00013907. The post-translational modifications of the PAR protein (poly ADP-ribose) are important for DNA stability. <br />
PDD00013907 is, as already stated, an anthraquinone which is a polycyclic aromatic hydrocarbon usually used in biopesticides as a pest repellant. Here it is considered as a free <scene name='82/829351/7jb/1'>ligand</scene> (of identification number on PDB: 7JB) that can bind to the <scene name='82/829351/Parg/1'>PARG</scene> creating the<scene name='82/829351/Complex/1'> protein complex 6HMM</scene>. <br />
=== Post-translational modifications and anthraquinone===<br />
There are several possible post-translational modifications to stabilize DNA. Most commonly there would be phosphorylation, acetylation or methylation <ref>PMID: 21037856</ref>. Another post-translational modification concerning the 6HMM protein is made on the poly(ADP-ribose) protein (PAR). PAR is composed of a repetition of ADP-ribose units linked through glycosidic ribose-ribose bonds <ref>doi: 10.1038/nature10404</ref>. This allows the repair of single-strand breaks on DNA <ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792.">DOI: 10.1021/acs.jmedchem.8b01407</ref>. PARG, a constituent of the 6HMM protein, will degrade PAR to allow the poly (ADP-ribose) polymerase (PARP) to free itself from the damaged site, that is now repaired, and completes as such reparation <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12.">PMID: 27689388</ref>.<br />
<br />
The anthraquinone PDD00013907 is a weakly active and cytotoxic anthraquinone 8a acting as a free ligand binding in the ADP-ribose binding site of the PARG. This PDD00013907 should lead to the inhibition of PARG, which is of interest in the search of novel cancer therapies <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. <br />
<br />
=== The mechanism ===<br />
As said previously, poly(ADP-ribosylation) is an important post-translational modification for DNA repair. The mechanism behind this repair relies on several factors. At first, the Poly (ADP-ribose) polymerase (PARP), more specifically the subtype [http://www.uniprot.org/uniprot/P09874 PARP1], will recognize and will bind to the single-stranded break on the DNA. It will then autophosphorylate due to NAD+ and form PAR chains. These will recruit other repair proteins to the site. <br />
<br />
The role of PARG is the hydrolyzation of the specific ribose-ribose bonds present in PAR which leads to its degradation and as such the reparation cycle will be finished<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/>. This degradation is important because without PARG the repair cycle cannot be completed <ref>PMID: 17548475</ref> and may lead to cell death. This is partially due to the still present PARP on the previously damaged site maintained by the non-degraded PAR <ref>PMID: 16140981</ref>. <br />
<br />
== Diseases and Relevance ==<br />
Due to the function of the protein poly (ADP-ribose) glycohydrolase PARG to be part of post-translational processes of DNA damage repair it could be used for new treatments in cancer therapy or for ther diseases. In cancer cells the rate of DNA damage is most probably higher than in normal cells. This could result from the considerably raised stress levels. A deficiency of PARG results in the cessing of the cell cycle and the following cell death<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/><ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>. Consequently, the inhibition of PARG might be a solution on how to destroy tumor cells, for example.<br />
<br />
For the PAR protein, there has already been a lot of research concerning novel treatments, but not for PARG. As there are no close homologues of PARG<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/>, this protein provides a potential target in drug discovery.<br />
<br />
As the protein in complex with the anthraquinone does not work properly anymore [http://www.rcsb.org/structure/6HMM], the described complex shows how an inhibited PARG might act in the cell. The goal of searched therapeutics is therefore to find a way to get the protein PARG into a complex that is acting similar to the 6HMM complex. For now, the research for anthraquinone as inhibitor has stopped as it is cytotoxic for the cell<ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>.<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Laurine Grimandihttps://proteopedia.org/index.php?title=Sandbox_Reserved_1657&diff=3500135Sandbox Reserved 16572022-01-11T16:02:33Z<p>Laurine Grimandi: </p>
<hr />
<div>{{5CZX}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==<scene name='86/868190/5czx_version_2_with_ligands/1'>5CZX</scene>==<br />
<StructureSection load='5czx' size='360' side='right' caption='Crystal structure of Notch3 NRR' scene='86/868190/5czx_version_2_with_ligands/1'><br />
<br />
<br />
== Structural highlights ==<br />
<br />
<br />
<scene name='86/868190/5czx_version_2_with_ligands/1'>5CZX</scene> stands for the <scene name='86/868190/Nrr_domain_alonecentre/4'>NRR (negative regulatory region)</scene> of the [https://www.uniprot.org/uniprot/Q9UM47 neurogenic locus notch homolog protein 3] in complex with 20358 [https://en.wikipedia.org/wiki/Fragment_antigen-binding Fab]. This NRR is made of <scene name='86/868190/4zlp_2_chains_nrr/1'>2 identical chain structures</scene> encoded by the [https://en.wikipedia.org/wiki/Notch_3 NOTCH3 gene](In this article, we will only focus on one of the two chains). It is composed of <scene name='86/868190/Lnr_domains/1'>three LIN12/Notch repeats and linker</scene> (LNRs respectively <scene name='86/868190/Lna_domain/1'>LNR-A</scene>,<scene name='86/868190/Lnb_domain/1'>LNR-B</scene>, <scene name='86/868190/Lrn_linker_bc/1'>LNR-B/C linker</scene> and <scene name='86/868190/Lnc/1'>LNR-C</scene> ) and a <scene name='86/868190/Hd/1'>heterodimerization domain (HD)</scene> composed by <scene name='86/868190/Hd-c/1'>HD-C</scene> and <scene name='86/868190/Hd-n/1'>HD-N</scene>.<ref name="oncogene">Bernasconi-Elias, P., Hu, T., Jenkins, D. et al. Characterization of activating mutations of NOTCH3 in T-cell acute lymphoblastic leukemia and anti-leukemic activity of NOTCH3 inhibitory antibodies. Oncogene 35, 6077–6086 (2016). https://doi.org/10.1038/onc.2016.133</ref>. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5czx OCA]. For a guided tour on the structure components in complex with [https://swissmodel.expasy.org/templates/5czx.2 20358 Fab] use [https://proteopedia.org/wiki/fgij/fg.htm?mol=5CZX FirstGlance].<br />
<br />
<table><tr><td colspan='3'><br><br />
</td></tr><tr id='gene'><td class="sblockLbl"><b>Gene</b></td><td class="sblockDat">NOTCH3</td></tr><br />
<tr id='Sources'><td class="sblockLbl"><b>Sources</b></td><td class="sblockDat"><span class='plainlinks'>Homo Sapiens, Humans</span></td></tr><tr id='Length'><td class="sblockLbl"><b>Length</b></td><td class="sblockDat">271 amino acids</td></tr><tr id='Theoretical weight'><td class="sblockLbl"><b>Theoretical weight</b></td><td class="sblockDat">30,1 KDa</td></tr><tr id='Biochemical function'><td class="sblockLbl"><b>Biochemical function</b></td><td class="sblockDat">Signaling receptor activity</td></tr><tr id='Biological process'><td class="sblockLbl"><b>Biological process</b></td><td class="sblockDat">Multicellular organism development</td></tr><tr id='Cellular component'><td class="sblockLbl"><b>Cellular component</b></td><td class="sblockDat">Integral component of membrane</td></tr><br />
<tr id='Ligands and Environments'><td class="sblockLbl"><b>Ligands and Environments</b></td><td class="sblockDat"><span class='plainlinks'>2x <scene name='86/868190/Nag/1'>NAG</scene>, 6x <scene name='86/868190/Ca2/1'>Ca2+</scene>, 10x <scene name='86/868190/Edo/1'>EDO</scene>, 3x Cl-</span></td></tr><br />
<tr id='resources'><td class="sblockLbl"><b>Resources</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/wiki/fgij/fg.htm?mol=5CZX FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5czx OCA], [https://www.ebi.ac.uk/pdbe/entry/search/index/?searchParams=%7B%22q_pdb_id%22:%5B%7B%22value%22:%225czx%22,%22condition1%22:%22AND%22,%22condition2%22:%22Contains%22%7D%5D,%22resultState%22:%7B%22tabIndex%22:0,%22paginationIndex%22:1,%22perPage%22:%2210%22,%22sortBy%22:%22Sort%20by%22%7D%7D PDBe], [https://www.rcsb.org/structure/5CZX RCSB], [http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl?pdbcode=5czx&template=protein.html&r=wiring&l=1&chain=A PDBsum]</span></td></tr><br />
</table><br />
<br />
<table><tr><td colspan='3'><br><br />
</td></tr><tr id='name'><td class="sblockLbl"><b>Name</b></td><td class="sblockDat"><span class='plainlinks'><scene name='86/868190/5czx_heavy_chain_labeled/1'>20358 Fab heavy chain</scene></span></td></tr><tr id='Sources'><td class="sblockLbl"><b>Sources</b></td><td class="sblockDat"><span class='plainlinks'>Homo Sapiens, Humans</span></td></tr><tr id='Length'><td class="sblockLbl"><b>Length</b></td><td class="sblockDat">226 amino acids</td></tr><tr id='Theoretical weight'><td class="sblockLbl"><b>Theoretical weight</b></td><td class="sblockDat">24,12 KDa</td></tr><br />
</table><br />
More informations are available on [https://www.ebi.ac.uk/pdbe/entry/pdb/5czx/protein/2 20358 Fab heavy chain].<br />
<br />
<table><tr><td colspan='3'><br><br />
</td></tr><tr id='name'><td class="sblockLbl"><b>Name</b></td><td class="sblockDat"><span class='plainlinks'><scene name='86/868190/5czx_light_chain_labeled/1'>20358 Fab light chain </scene></span></td></tr><tr id='Sources'><td class="sblockLbl"><b>Sources</b></td><td class="sblockDat"><span class='plainlinks'>Homo Sapiens, Humans</span></td></tr><tr id='Length'><td class="sblockLbl"><b>Length</b></td><td class="sblockDat">214 amino acids</td></tr><tr id='Theoretical weight'><td class="sblockLbl"><b>Theoretical weight</b></td><td class="sblockDat">23,39 KDa</td></tr><br />
</table><br />
More informations are available on [https://www.ebi.ac.uk/pdbe/entry/pdb/5czx/protein/3 20358 Fab light chain].<br />
<br />
<br />
<br />
== Function ==<br />
<br />
'''[https://www.creative-diagnostics.com/notch-family.htm NOTCH family] :''' The NOTCH family encodes [https://en.wikipedia.org/wiki/Cell_surface_receptor transmembrane receptor proteins] that are involved in cell fate determination during development. In the drosophila <ref name=Drosophila >DOI:10.1126/science.aab0988</ref> adult midgut, intestinal [https://en.wikipedia.org/wiki/Stem_cell stem cells] (ISCs) produce two types of daughter cells, the [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3837124/#:~:text=Enterocytes%20are%20specialized%20to%20absorb,along%20the%20crypt%2Dvillus%20axis. nutrient-absorbing enterocytes (ECs)] and [https://en.wikipedia.org/wiki/Enteroendocrine_cell secretory enteroendocrine cells]. Notch signalling between intestinal stem cells and their daughter cells guides cell specification. ISCs with elevated levels of the Notch Delta ligand more primarily activate the Notch signalling pathway in daughter cells and cause them to become ECs. However, ISCs having low levels of Notch Delta ligand direct daughter cells to become enteroendocrine cells. <br />
The NOTCH gene family in humans <ref name=Function>DOI:10.1038/sj.onc.1203276</ref> has a link with the Drosophila Notch gene. Members of the NOTCH gene family encode transmembrane receptor proteins that are useful to determine the cell fate during development.<br />
<br />
'''5CZX :''' 5CZX receives a signal and transmits it in the cell to initiate a change in cell activity.It can also used in the neuron fate commitment, artery morphogenesis or the regulation of NOTCH signaling pathway <br />
<br />
== Disease ==<br />
<br />
It is well understood that the [https://en.wikipedia.org/wiki/Notch_proteins Notch] receptors plays an important role in cancer development in mammals and changes the activity of these receptors which dysfunction can be associated with various benign and malignant diseases such as [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6142501/ T-ALL (T-lineage acute lymphoblastic leukemia)]. T-ALL is characterized by the uncontrolled proliferation of T-cell [https://en.wikipedia.org/wiki/Lymphoblast lymphoblasts] in the blood, the brown marrow and the tissues. These oncogenic mechanisms of the ''Notch'' receptors are dependant on its intracelluclar signaling. Therefore, in order to understand how the cancer develops due to these receptors, it is necessary to understand the [https://en.wikipedia.org/wiki/Notch_signaling_pathway Notch pathway]. <br />
<br />
As an example, the target genes in the pathway of [https://en.wikipedia.org/wiki/Notch_3 NOTCH3] or other subtypes of the ''Notch'' receptors are expressed by a variety of translocation, [https://en.wikipedia.org/wiki/Post-translational_modification post-translational modifications] and activation of ligands associated to it. Following translation, Furin-like convertase modifies the ''Notch'' receptor by proteolytic cleavage at site 1 (S1) and transported to the cell surface held together by the <scene name='86/868190/Hd/1'>heterodimerization (HD) domain</scene>. The ''Notch'' receptor on the signal‐receiving cell binds to a ligand on the cell surface of a neighboring signal‐sending cell, causing it to get activated. This binding causes a change in the conformation of the receptor. <scene name='86/868190/S2_domaintrue/5'>Site 2</scene>, present within the <scene name='86/868190/Nrr_domain_alonecentre/2'>negative regulatory region (NRR) domain</scene>, is thus exposed for cleavage by a disintegrin and metalloprotease (ADAM). Notch cleavage at <scene name='86/868190/S2_domaintrue/5'>S2</scene> generates the membrane‐anchored Notch extracellular truncation (NEXT) fragment, a substrate for the γ‐secretase complex. Thus, the ''Notch'' receptor is cleaved by the γ-secretase complex. Following γ-secretase cleavage, the intracellular domain (ICD) of NOTCH3 translocates to the nucleus where it interacts with the DNA-binding factor RBPJ and co-activators of the [https://en.wikipedia.org/wiki/MAML1 mastermind-like (MAML)] family to form a transcriptional activation complex. <ref>doi:10.1634/theoncologist.2017-0677</ref><br />
<br />
<scene name='86/868190/Nrr_domain_alonecentre/2'>NRR</scene> mutations act by destabilizing or completely unfolding the <scene name='86/868190/Hd/1'>HD domain</scene>, relaxing the interface that protects the <scene name='86/868190/S2_domaintrue/5'>S2</scene> site. These mutations associated with the <scene name='86/868190/Hd/1'>HD domain</scene> in the <scene name='86/868190/Nrr_domain_alonecentre/2'>NRR domain</scene> lead to increased Notch signaling by way increased expression of the target gene that leads to abnormal levels of the ICD of Notch. These abnormally high levels of ICD of the Notch receptors are understood to be the cause of the development of several different human cancers.<ref name="oncogene">Bernasconi-Elias, P., Hu, T., Jenkins, D. et al. Characterization of activating mutations of NOTCH3 in T-cell acute lymphoblastic leukemia and anti-leukemic activity of NOTCH3 inhibitory antibodies. Oncogene 35, 6077–6086 (2016). https://doi.org/10.1038/onc.2016.133</ref> Activating mutations of two different regions of [https://en.wikipedia.org/wiki/Notch_1 NOTCH1] were present in >50% of [https://science.sciencemag.org/content/306/5694/269 T-cell acute lymphoblastic leukemia (T-ALL)]. Abnormally high amounts of NOTCH3 were reported to be in approximately 10–25% of ovarian adenocarcinomas. NOTCH3 mutations have also been reported in around 1% of head and neck squamous carcinomas, ovarian cancers, and lung adenocarcinoma. <ref name="oncogene" /><br />
<br />
Further research on the NOTCH3 activation is key to providing a way forward to identify the different human cancers that could potentially respond to therapy based on [https://www.nature.com/articles/onc2016133#Abs1 NOTCH3-selective inhibitory antibodies].<ref name="oncogene" /> Furthermore, the development of well-characterized diagnostic reagents and biomarkers tests related to the ''Notch'' pathway is essential to fully deciphering the complex role of ''Notch'' receptors in cancer, thereby promoting more successful trials of similar ''Notch'' pathway inhibitors as a plausible treatment for cancer patients.<ref name="roles">doi:10.1146/annurev-pathol-052016-100127</ref><br />
<br />
== Relevance ==<br />
<br />
The ''Notch'' signalling pathway regulates cell-to-cell interaction, [https://en.wikipedia.org/wiki/Embryonic_development embryogenesis] as well as various other biological functions in adult tissues. It is a highly conserved pathway. Its relevance and clinical significance lies in the mutations of the ''Notch'' gene that have been identified as a contributing factor to an extensive range of cancers in mammals. These mutations can change the activity of the pathway rendering it capable of causing [https://pubmed.ncbi.nlm.nih.gov/22306179/ various diseases] depending on the sub-type of the targeted ''Notch'' receptor and more importantly, causing it to play an oncogenic or tumor-suppressive role.<ref name="roles" /><br />
<br />
The ''Notch'' signalling pathway has been studied comprehensively and various aspects of this pathway are very well known. Despite this, it is essential to study the pathway further, so as to understand the role it plays in cancer development and explore novel treatment strategies focusing on the ''Notch'' pathway.<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Laurine Grimandihttps://proteopedia.org/index.php?title=Sandbox_Reserved_1657&diff=3499993Sandbox Reserved 16572022-01-10T20:59:41Z<p>Laurine Grimandi: </p>
<hr />
<div>{{5CZX}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==<scene name='86/868190/5czx_version_2_with_ligands/1'>5CZX</scene>==<br />
<StructureSection load='5czx' size='360' side='right' caption='Crystal structure of Notch3 NRR' scene='86/868190/5czx_version_2_with_ligands/1'><br />
<br />
<br />
== Structural highlights ==<br />
<br />
<br />
<scene name='86/868190/5czx_version_2_with_ligands/1'>5CZX</scene> stands for the <scene name='86/868190/Nrr_domain_alonecentre/4'>NRR (negative regulatory region)</scene> of the [https://www.uniprot.org/uniprot/Q9UM47 neurogenic locus notch homolog protein 3] in complex with 20358 [https://en.wikipedia.org/wiki/Fragment_antigen-binding Fab]. This NRR is made of <scene name='86/868190/4zlp_2_chains_nrr/1'>2 identical chain structures</scene> encoded by the [https://en.wikipedia.org/wiki/Notch_3 NOTCH3 gene](In this article, we will only focus on one of the two chains). It is composed of <scene name='86/868190/Lnr_domains/1'>three LIN12/Notch repeats and linker</scene> (LNRs respectively <scene name='86/868190/Lna_domain/1'>LNR-A</scene>,<scene name='86/868190/Lnb_domain/1'>LNR-B</scene>, <scene name='86/868190/Lrn_linker_bc/1'>LNR-B/C linker</scene> and <scene name='86/868190/Lnc/1'>LNR-C</scene> ) and a <scene name='86/868190/Hd/1'>heterodimerization domain (HD)</scene> composed by <scene name='86/868190/Hd-c/1'>HD-C</scene> and <scene name='86/868190/Hd-n/1'>HD-N</scene>.<ref name="oncogene">Bernasconi-Elias, P., Hu, T., Jenkins, D. et al. Characterization of activating mutations of NOTCH3 in T-cell acute lymphoblastic leukemia and anti-leukemic activity of NOTCH3 inhibitory antibodies. Oncogene 35, 6077–6086 (2016). https://doi.org/10.1038/onc.2016.133</ref>. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5czx OCA]. For a guided tour on the structure components in complex with [https://swissmodel.expasy.org/templates/5czx.2 20358 Fab] use [https://proteopedia.org/wiki/fgij/fg.htm?mol=5CZX FirstGlance].<br />
<br />
<table><tr><td colspan='3'><br><br />
</td></tr><tr id='gene'><td class="sblockLbl"><b>Gene</b></td><td class="sblockDat">NOTCH3</td></tr><br />
<tr id='Sources'><td class="sblockLbl"><b>Sources</b></td><td class="sblockDat"><span class='plainlinks'>Homo Sapiens, Humans</span></td></tr><tr id='Length'><td class="sblockLbl"><b>Length</b></td><td class="sblockDat">271 amino acids</td></tr><tr id='Theoretical weight'><td class="sblockLbl"><b>Theoretical weight</b></td><td class="sblockDat">30,1 KDa</td></tr><tr id='Biochemical function'><td class="sblockLbl"><b>Biochemical function</b></td><td class="sblockDat">Signaling receptor activity</td></tr><tr id='Biological process'><td class="sblockLbl"><b>Biological process</b></td><td class="sblockDat">Multicellular organism development</td></tr><tr id='Cellular component'><td class="sblockLbl"><b>Cellular component</b></td><td class="sblockDat">Integral component of membrane</td></tr><br />
<tr id='Ligands and Environments'><td class="sblockLbl"><b>Ligands and Environments</b></td><td class="sblockDat"><span class='plainlinks'>2x <scene name='86/868190/Nag/1'>NAG</scene>, 6x <scene name='86/868190/Ca2/1'>Ca2+</scene>, 10x <scene name='86/868190/Edo/1'>EDO</scene>, 3x Cl-</span></td></tr><br />
<tr id='resources'><td class="sblockLbl"><b>Resources</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/wiki/fgij/fg.htm?mol=5CZX FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5czx OCA], [https://www.ebi.ac.uk/pdbe/entry/search/index/?searchParams=%7B%22q_pdb_id%22:%5B%7B%22value%22:%225czx%22,%22condition1%22:%22AND%22,%22condition2%22:%22Contains%22%7D%5D,%22resultState%22:%7B%22tabIndex%22:0,%22paginationIndex%22:1,%22perPage%22:%2210%22,%22sortBy%22:%22Sort%20by%22%7D%7D PDBe], [https://www.rcsb.org/structure/5CZX RCSB], [http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl?pdbcode=5czx&template=protein.html&r=wiring&l=1&chain=A PDBsum]</span></td></tr><br />
</table><br />
<br />
<table><tr><td colspan='3'><br><br />
</td></tr><tr id='name'><td class="sblockLbl"><b>Name</b></td><td class="sblockDat"><span class='plainlinks'><scene name='86/868190/5czx_heavy_chain_labeled/1'>20358 Fab heavy chain</scene></span></td></tr><tr id='Sources'><td class="sblockLbl"><b>Sources</b></td><td class="sblockDat"><span class='plainlinks'>Homo Sapiens, Humans</span></td></tr><tr id='Length'><td class="sblockLbl"><b>Length</b></td><td class="sblockDat">226 amino acids</td></tr><tr id='Theoretical weight'><td class="sblockLbl"><b>Theoretical weight</b></td><td class="sblockDat">24,12 KDa</td></tr><br />
</table><br />
More informations are available on [https://www.ebi.ac.uk/pdbe/entry/pdb/5czx/protein/2 20358 Fab heavy chain].<br />
<br />
<table><tr><td colspan='3'><br><br />
</td></tr><tr id='name'><td class="sblockLbl"><b>Name</b></td><td class="sblockDat"><span class='plainlinks'><scene name='86/868190/5czx_light_chain_labeled/1'>20358 Fab light chain </scene></span></td></tr><tr id='Sources'><td class="sblockLbl"><b>Sources</b></td><td class="sblockDat"><span class='plainlinks'>Homo Sapiens, Humans</span></td></tr><tr id='Length'><td class="sblockLbl"><b>Length</b></td><td class="sblockDat">214 amino acids</td></tr><tr id='Theoretical weight'><td class="sblockLbl"><b>Theoretical weight</b></td><td class="sblockDat">23,39 KDa</td></tr><br />
</table><br />
More informations are available on [https://www.ebi.ac.uk/pdbe/entry/pdb/5czx/protein/3 20358 Fab light chain].<br />
<br />
<br />
<br />
== Regulation of cell-to-cell interaction : embryogenesis ==<br />
<br />
The Notch signaling pathway regulates cell-to-cell interaction, embryogenesis (lien bleu embryogenesis) as well as various other biological functions in adult tissues of metazoans.<br />
The Notch signaling pathway derives its name from the NOTCH receptors, which are activated through ligands located on the cell membrane of other cells (sending cells). The NOTCH receptor is composed of three domains, a single transmembrane domain (NTM), a notch intracellular domain (NICD) and an extracellular domain (NEC). The NEC contains the <scene name='86/868190/Nrr_domain_alonecentre/4'>NRR (negative regulatory region)</scene> (which contains an <scene name='86/868190/Lnr_module_from_human_notch1/1'>LNR module </scene> and a <scene name='86/868190/Hd/1'>heterodimerization domain (HD)</scene> composed by <scene name='86/868190/Hd-c/1'>HD-C</scene> and <scene name='86/868190/Hd-n/1'>HD-N</scene>. Upon ligand binding to the NEC, the Notch receptor undergoes cleavage reactions, releasing the NICD into the cytosol. The NICD binds to the complex of proteins, which translocate into the nucleus and activate Notch target genes involved in cellular proliferation, differentiation and apoptosis.<br />
<br />
We define the roles of two regions at the C-terminal end of NEC that participate in maintaining the integrity of resting Notch receptors through distinct mechanisms. The first region, a hydrophobic, previously uncharacterized portion of NEC, is sufficient to form stable complexes with the extracellular portion of NTM. The second region, consisting of the <scene name='86/868190/Lnr_domains/1'>three LIN12/Notch repeats and linker</scene> (<scene name='86/868190/Lna_domain/1'>LNR-A</scene>,<scene name='86/868190/Lnb_domain/1'>LNR-B</scene>, <scene name='86/868190/Lrn_linker_bc/1'>LNR-B/C linker</scene> and <scene name='86/868190/Lnc/1'>LNR-C</scene> ),, is not needed for heterodimerization but acts to protect NTM from ligand-independent cleavage by metalloproteases. Together, these two contiguous regions of NEC impose crucial restraints that prevent premature Notch receptor activation.<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
== Function ==<br />
<br />
'''[https://www.creative-diagnostics.com/notch-family.htm NOTCH family] :''' The NOTCH family encodes [https://en.wikipedia.org/wiki/Cell_surface_receptor transmembrane receptor proteins] that are involved in cell fate determination during development. In the drosophila <ref name=Drosophila >DOI:10.1126/science.aab0988</ref> adult midgut, intestinal [https://en.wikipedia.org/wiki/Stem_cell stem cells] (ISCs) produce two types of daughter cells, the [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3837124/#:~:text=Enterocytes%20are%20specialized%20to%20absorb,along%20the%20crypt%2Dvillus%20axis. nutrient-absorbing enterocytes (ECs)] and [https://en.wikipedia.org/wiki/Enteroendocrine_cell secretory enteroendocrine cells]. Notch signalling between intestinal stem cells and their daughter cells guides cell specification. ISCs with elevated levels of the Notch Delta ligand more primarily activate the Notch signalling pathway in daughter cells and cause them to become ECs. However, ISCs having low levels of Notch Delta ligand direct daughter cells to become enteroendocrine cells. <br />
The NOTCH gene family in humans <ref name=Function>DOI:10.1038/sj.onc.1203276</ref> has a link with the Drosophila Notch gene. Members of the NOTCH gene family encode transmembrane receptor proteins that are useful to determine the cell fate during development.<br />
<br />
'''5CZX :''' 5CZX receives a signal and transmits it in the cell to initiate a change in cell activity.It can also used in the neuron fate commitment, artery morphogenesis or the regulation of NOTCH signaling pathway <br />
<br />
== Disease ==<br />
<br />
It is well understood that the [https://en.wikipedia.org/wiki/Notch_proteins Notch] receptors plays an important role in cancer development in mammals and changes the activity of these receptors which dysfunction can be associated with various benign and malignant diseases such as [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6142501/ T-ALL (T-lineage acute lymphoblastic leukemia)]. T-ALL is characterized by the uncontrolled proliferation of T-cell [https://en.wikipedia.org/wiki/Lymphoblast lymphoblasts] in the blood, the brown marrow and the tissues. These oncogenic mechanisms of the ''Notch'' receptors are dependant on its intracelluclar signaling. Therefore, in order to understand how the cancer develops due to these receptors, it is necessary to understand the [https://en.wikipedia.org/wiki/Notch_signaling_pathway Notch pathway]. <br />
<br />
As an example, the target genes in the pathway of [https://en.wikipedia.org/wiki/Notch_3 NOTCH3] or other subtypes of the ''Notch'' receptors are expressed by a variety of translocation, [https://en.wikipedia.org/wiki/Post-translational_modification post-translational modifications] and activation of ligands associated to it. Following translation, Furin-like convertase modifies the ''Notch'' receptor by proteolytic cleavage at site 1 (S1) and transported to the cell surface held together by the <scene name='86/868190/Hd/1'>heterodimerization (HD) domain</scene>. The ''Notch'' receptor on the signal‐receiving cell binds to a ligand on the cell surface of a neighboring signal‐sending cell, causing it to get activated. This binding causes a change in the conformation of the receptor. <scene name='86/868190/S2_domaintrue/5'>Site 2</scene>, present within the <scene name='86/868190/Nrr_domain_alonecentre/2'>negative regulatory region (NRR) domain</scene>, is thus exposed for cleavage by a disintegrin and metalloprotease (ADAM). Notch cleavage at <scene name='86/868190/S2_domaintrue/5'>S2</scene> generates the membrane‐anchored Notch extracellular truncation (NEXT) fragment, a substrate for the γ‐secretase complex. Thus, the ''Notch'' receptor is cleaved by the γ-secretase complex. Following γ-secretase cleavage, the intracellular domain (ICD) of NOTCH3 translocates to the nucleus where it interacts with the DNA-binding factor RBPJ and co-activators of the [https://en.wikipedia.org/wiki/MAML1 mastermind-like (MAML)] family to form a transcriptional activation complex. <ref>doi:10.1634/theoncologist.2017-0677</ref><br />
<br />
<scene name='86/868190/Nrr_domain_alonecentre/2'>NRR</scene> mutations act by destabilizing or completely unfolding the <scene name='86/868190/Hd/1'>HD domain</scene>, relaxing the interface that protects the <scene name='86/868190/S2_domaintrue/5'>S2</scene> site. These mutations associated with the <scene name='86/868190/Hd/1'>HD domain</scene> in the <scene name='86/868190/Nrr_domain_alonecentre/2'>NRR domain</scene> lead to increased Notch signaling by way increased expression of the target gene that leads to abnormal levels of the ICD of Notch. These abnormally high levels of ICD of the Notch receptors are understood to be the cause of the development of several different human cancers.<ref name="oncogene">Bernasconi-Elias, P., Hu, T., Jenkins, D. et al. Characterization of activating mutations of NOTCH3 in T-cell acute lymphoblastic leukemia and anti-leukemic activity of NOTCH3 inhibitory antibodies. Oncogene 35, 6077–6086 (2016). https://doi.org/10.1038/onc.2016.133</ref> Activating mutations of two different regions of [https://en.wikipedia.org/wiki/Notch_1 NOTCH1] were present in >50% of [https://science.sciencemag.org/content/306/5694/269 T-cell acute lymphoblastic leukemia (T-ALL)]. Abnormally high amounts of NOTCH3 were reported to be in approximately 10–25% of ovarian adenocarcinomas. NOTCH3 mutations have also been reported in around 1% of head and neck squamous carcinomas, ovarian cancers, and lung adenocarcinoma. <ref name="oncogene" /><br />
<br />
Further research on the NOTCH3 activation is key to providing a way forward to identify the different human cancers that could potentially respond to therapy based on [https://www.nature.com/articles/onc2016133#Abs1 NOTCH3-selective inhibitory antibodies].<ref name="oncogene" /> Furthermore, the development of well-characterized diagnostic reagents and biomarkers tests related to the ''Notch'' pathway is essential to fully deciphering the complex role of ''Notch'' receptors in cancer, thereby promoting more successful trials of similar ''Notch'' pathway inhibitors as a plausible treatment for cancer patients.<ref name="roles">doi:10.1146/annurev-pathol-052016-100127</ref><br />
<br />
== Relevance ==<br />
<br />
The ''Notch'' signalling pathway regulates cell-to-cell interaction, [https://en.wikipedia.org/wiki/Embryonic_development embryogenesis] as well as various other biological functions in adult tissues. It is a highly conserved pathway. Its relevance and clinical significance lies in the mutations of the ''Notch'' gene that have been identified as a contributing factor to an extensive range of cancers in mammals. These mutations can change the activity of the pathway rendering it capable of causing [https://pubmed.ncbi.nlm.nih.gov/22306179/ various diseases] depending on the sub-type of the targeted ''Notch'' receptor and more importantly, causing it to play an oncogenic or tumor-suppressive role.<ref name="roles" /><br />
<br />
The ''Notch'' signalling pathway has been studied comprehensively and various aspects of this pathway are very well known. Despite this, it is essential to study the pathway further, so as to understand the role it plays in cancer development and explore novel treatment strategies focusing on the ''Notch'' pathway.<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Laurine Grimandihttps://proteopedia.org/index.php?title=Sandbox_Reserved_1657&diff=3499986Sandbox Reserved 16572022-01-10T20:17:39Z<p>Laurine Grimandi: </p>
<hr />
<div>{{5CZX}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==<scene name='86/868190/5czx_version_2_with_ligands/1'>5CZX</scene>==<br />
<StructureSection load='5czx' size='360' side='right' caption='Crystal structure of Notch3 NRR' scene='86/868190/5czx_version_2_with_ligands/1'><br />
<br />
<br />
== Structural highlights ==<br />
<br />
<scene name='86/868190/Lnr_module_from_human_notch1/1'>LNR module from NOTCH1</scene><br />
<br />
<scene name='86/868190/5czx_version_2_with_ligands/1'>5CZX</scene> stands for the <scene name='86/868190/Nrr_domain_alonecentre/4'>NRR (negative regulatory region)</scene> of the [https://www.uniprot.org/uniprot/Q9UM47 neurogenic locus notch homolog protein 3] in complex with 20358 [https://en.wikipedia.org/wiki/Fragment_antigen-binding Fab]. This NRR is made of <scene name='86/868190/4zlp_2_chains_nrr/1'>2 identical chain structures</scene> encoded by the [https://en.wikipedia.org/wiki/Notch_3 NOTCH3 gene](In this article, we will only focus on one of the two chains). It is composed of <scene name='86/868190/Lnr_domains/1'>three LIN12/Notch repeats and linker</scene> (LNRs respectively <scene name='86/868190/Lna_domain/1'>LNR-A</scene>,<scene name='86/868190/Lnb_domain/1'>LNR-B</scene>, <scene name='86/868190/Lrn_linker_bc/1'>LNR-B/C linker</scene> and <scene name='86/868190/Lnc/1'>LNR-C</scene> ) and a <scene name='86/868190/Hd/1'>heterodimerization domain (HD)</scene> composed by <scene name='86/868190/Hd-c/1'>HD-C</scene> and <scene name='86/868190/Hd-n/1'>HD-N</scene>.<ref name="oncogene">Bernasconi-Elias, P., Hu, T., Jenkins, D. et al. Characterization of activating mutations of NOTCH3 in T-cell acute lymphoblastic leukemia and anti-leukemic activity of NOTCH3 inhibitory antibodies. Oncogene 35, 6077–6086 (2016). https://doi.org/10.1038/onc.2016.133</ref>. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5czx OCA]. For a guided tour on the structure components in complex with [https://swissmodel.expasy.org/templates/5czx.2 20358 Fab] use [https://proteopedia.org/wiki/fgij/fg.htm?mol=5CZX FirstGlance].<br />
<br />
<table><tr><td colspan='3'><br><br />
</td></tr><tr id='gene'><td class="sblockLbl"><b>Gene</b></td><td class="sblockDat">NOTCH3</td></tr><br />
<tr id='Sources'><td class="sblockLbl"><b>Sources</b></td><td class="sblockDat"><span class='plainlinks'>Homo Sapiens, Humans</span></td></tr><tr id='Length'><td class="sblockLbl"><b>Length</b></td><td class="sblockDat">271 amino acids</td></tr><tr id='Theoretical weight'><td class="sblockLbl"><b>Theoretical weight</b></td><td class="sblockDat">30,1 KDa</td></tr><tr id='Biochemical function'><td class="sblockLbl"><b>Biochemical function</b></td><td class="sblockDat">Signaling receptor activity</td></tr><tr id='Biological process'><td class="sblockLbl"><b>Biological process</b></td><td class="sblockDat">Multicellular organism development</td></tr><tr id='Cellular component'><td class="sblockLbl"><b>Cellular component</b></td><td class="sblockDat">Integral component of membrane</td></tr><br />
<tr id='Ligands and Environments'><td class="sblockLbl"><b>Ligands and Environments</b></td><td class="sblockDat"><span class='plainlinks'>2x <scene name='86/868190/Nag/1'>NAG</scene>, 6x <scene name='86/868190/Ca2/1'>Ca2+</scene>, 10x <scene name='86/868190/Edo/1'>EDO</scene>, 3x Cl-</span></td></tr><br />
<tr id='resources'><td class="sblockLbl"><b>Resources</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/wiki/fgij/fg.htm?mol=5CZX FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5czx OCA], [https://www.ebi.ac.uk/pdbe/entry/search/index/?searchParams=%7B%22q_pdb_id%22:%5B%7B%22value%22:%225czx%22,%22condition1%22:%22AND%22,%22condition2%22:%22Contains%22%7D%5D,%22resultState%22:%7B%22tabIndex%22:0,%22paginationIndex%22:1,%22perPage%22:%2210%22,%22sortBy%22:%22Sort%20by%22%7D%7D PDBe], [https://www.rcsb.org/structure/5CZX RCSB], [http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl?pdbcode=5czx&template=protein.html&r=wiring&l=1&chain=A PDBsum]</span></td></tr><br />
</table><br />
<br />
<table><tr><td colspan='3'><br><br />
</td></tr><tr id='name'><td class="sblockLbl"><b>Name</b></td><td class="sblockDat"><span class='plainlinks'><scene name='86/868190/5czx_heavy_chain_labeled/1'>20358 Fab heavy chain</scene></span></td></tr><tr id='Sources'><td class="sblockLbl"><b>Sources</b></td><td class="sblockDat"><span class='plainlinks'>Homo Sapiens, Humans</span></td></tr><tr id='Length'><td class="sblockLbl"><b>Length</b></td><td class="sblockDat">226 amino acids</td></tr><tr id='Theoretical weight'><td class="sblockLbl"><b>Theoretical weight</b></td><td class="sblockDat">24,12 KDa</td></tr><br />
</table><br />
More informations are available on [https://www.ebi.ac.uk/pdbe/entry/pdb/5czx/protein/2 20358 Fab heavy chain].<br />
<br />
<table><tr><td colspan='3'><br><br />
</td></tr><tr id='name'><td class="sblockLbl"><b>Name</b></td><td class="sblockDat"><span class='plainlinks'><scene name='86/868190/5czx_light_chain_labeled/1'>20358 Fab light chain </scene></span></td></tr><tr id='Sources'><td class="sblockLbl"><b>Sources</b></td><td class="sblockDat"><span class='plainlinks'>Homo Sapiens, Humans</span></td></tr><tr id='Length'><td class="sblockLbl"><b>Length</b></td><td class="sblockDat">214 amino acids</td></tr><tr id='Theoretical weight'><td class="sblockLbl"><b>Theoretical weight</b></td><td class="sblockDat">23,39 KDa</td></tr><br />
</table><br />
More informations are available on [https://www.ebi.ac.uk/pdbe/entry/pdb/5czx/protein/3 20358 Fab light chain].<br />
<br />
== Function ==<br />
<br />
'''[https://www.creative-diagnostics.com/notch-family.htm NOTCH family] :''' The NOTCH family encodes [https://en.wikipedia.org/wiki/Cell_surface_receptor transmembrane receptor proteins] that are involved in cell fate determination during development. In the drosophila <ref name=Drosophila >DOI:10.1126/science.aab0988</ref> adult midgut, intestinal [https://en.wikipedia.org/wiki/Stem_cell stem cells] (ISCs) produce two types of daughter cells, the [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3837124/#:~:text=Enterocytes%20are%20specialized%20to%20absorb,along%20the%20crypt%2Dvillus%20axis. nutrient-absorbing enterocytes (ECs)] and [https://en.wikipedia.org/wiki/Enteroendocrine_cell secretory enteroendocrine cells]. Notch signalling between intestinal stem cells and their daughter cells guides cell specification. ISCs with elevated levels of the Notch Delta ligand more primarily activate the Notch signalling pathway in daughter cells and cause them to become ECs. However, ISCs having low levels of Notch Delta ligand direct daughter cells to become enteroendocrine cells. <br />
The NOTCH gene family in humans <ref name=Function>DOI:10.1038/sj.onc.1203276</ref> has a link with the Drosophila Notch gene. Members of the NOTCH gene family encode transmembrane receptor proteins that are useful to determine the cell fate during development.<br />
<br />
'''5CZX :''' 5CZX receives a signal and transmits it in the cell to initiate a change in cell activity.It can also used in the neuron fate commitment, artery morphogenesis or the regulation of NOTCH signaling pathway <br />
<br />
== Disease ==<br />
<br />
It is well understood that the [https://en.wikipedia.org/wiki/Notch_proteins Notch] receptors plays an important role in cancer development in mammals and changes the activity of these receptors which dysfunction can be associated with various benign and malignant diseases such as [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6142501/ T-ALL (T-lineage acute lymphoblastic leukemia)]. T-ALL is characterized by the uncontrolled proliferation of T-cell [https://en.wikipedia.org/wiki/Lymphoblast lymphoblasts] in the blood, the brown marrow and the tissues. These oncogenic mechanisms of the ''Notch'' receptors are dependant on its intracelluclar signaling. Therefore, in order to understand how the cancer develops due to these receptors, it is necessary to understand the [https://en.wikipedia.org/wiki/Notch_signaling_pathway Notch pathway]. <br />
<br />
As an example, the target genes in the pathway of [https://en.wikipedia.org/wiki/Notch_3 NOTCH3] or other subtypes of the ''Notch'' receptors are expressed by a variety of translocation, [https://en.wikipedia.org/wiki/Post-translational_modification post-translational modifications] and activation of ligands associated to it. Following translation, Furin-like convertase modifies the ''Notch'' receptor by proteolytic cleavage at site 1 (S1) and transported to the cell surface held together by the <scene name='86/868190/Hd/1'>heterodimerization (HD) domain</scene>. The ''Notch'' receptor on the signal‐receiving cell binds to a ligand on the cell surface of a neighboring signal‐sending cell, causing it to get activated. This binding causes a change in the conformation of the receptor. <scene name='86/868190/S2_domaintrue/5'>Site 2</scene>, present within the <scene name='86/868190/Nrr_domain_alonecentre/2'>negative regulatory region (NRR) domain</scene>, is thus exposed for cleavage by a disintegrin and metalloprotease (ADAM). Notch cleavage at <scene name='86/868190/S2_domaintrue/5'>S2</scene> generates the membrane‐anchored Notch extracellular truncation (NEXT) fragment, a substrate for the γ‐secretase complex. Thus, the ''Notch'' receptor is cleaved by the γ-secretase complex. Following γ-secretase cleavage, the intracellular domain (ICD) of NOTCH3 translocates to the nucleus where it interacts with the DNA-binding factor RBPJ and co-activators of the [https://en.wikipedia.org/wiki/MAML1 mastermind-like (MAML)] family to form a transcriptional activation complex. <ref>doi:10.1634/theoncologist.2017-0677</ref><br />
<br />
<scene name='86/868190/Nrr_domain_alonecentre/2'>NRR</scene> mutations act by destabilizing or completely unfolding the <scene name='86/868190/Hd/1'>HD domain</scene>, relaxing the interface that protects the <scene name='86/868190/S2_domaintrue/5'>S2</scene> site. These mutations associated with the <scene name='86/868190/Hd/1'>HD domain</scene> in the <scene name='86/868190/Nrr_domain_alonecentre/2'>NRR domain</scene> lead to increased Notch signaling by way increased expression of the target gene that leads to abnormal levels of the ICD of Notch. These abnormally high levels of ICD of the Notch receptors are understood to be the cause of the development of several different human cancers.<ref name="oncogene">Bernasconi-Elias, P., Hu, T., Jenkins, D. et al. Characterization of activating mutations of NOTCH3 in T-cell acute lymphoblastic leukemia and anti-leukemic activity of NOTCH3 inhibitory antibodies. Oncogene 35, 6077–6086 (2016). https://doi.org/10.1038/onc.2016.133</ref> Activating mutations of two different regions of [https://en.wikipedia.org/wiki/Notch_1 NOTCH1] were present in >50% of [https://science.sciencemag.org/content/306/5694/269 T-cell acute lymphoblastic leukemia (T-ALL)]. Abnormally high amounts of NOTCH3 were reported to be in approximately 10–25% of ovarian adenocarcinomas. NOTCH3 mutations have also been reported in around 1% of head and neck squamous carcinomas, ovarian cancers, and lung adenocarcinoma. <ref name="oncogene" /><br />
<br />
Further research on the NOTCH3 activation is key to providing a way forward to identify the different human cancers that could potentially respond to therapy based on [https://www.nature.com/articles/onc2016133#Abs1 NOTCH3-selective inhibitory antibodies].<ref name="oncogene" /> Furthermore, the development of well-characterized diagnostic reagents and biomarkers tests related to the ''Notch'' pathway is essential to fully deciphering the complex role of ''Notch'' receptors in cancer, thereby promoting more successful trials of similar ''Notch'' pathway inhibitors as a plausible treatment for cancer patients.<ref name="roles">doi:10.1146/annurev-pathol-052016-100127</ref><br />
<br />
== Relevance ==<br />
<br />
The ''Notch'' signalling pathway regulates cell-to-cell interaction, [https://en.wikipedia.org/wiki/Embryonic_development embryogenesis] as well as various other biological functions in adult tissues. It is a highly conserved pathway. Its relevance and clinical significance lies in the mutations of the ''Notch'' gene that have been identified as a contributing factor to an extensive range of cancers in mammals. These mutations can change the activity of the pathway rendering it capable of causing [https://pubmed.ncbi.nlm.nih.gov/22306179/ various diseases] depending on the sub-type of the targeted ''Notch'' receptor and more importantly, causing it to play an oncogenic or tumor-suppressive role.<ref name="roles" /><br />
<br />
The ''Notch'' signalling pathway has been studied comprehensively and various aspects of this pathway are very well known. Despite this, it is essential to study the pathway further, so as to understand the role it plays in cancer development and explore novel treatment strategies focusing on the ''Notch'' pathway.<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Laurine Grimandi