{{Sandbox_ESBS_2019}}
==6HMM==
<StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''>
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The 6HMM protein is a human[[ poly (ADP-ribose) glycohydrolase]]. It is an enzyme that will catalyze the hydrolysis of glycosides, here more specifically it will produce a free ADP-ribose. This protein is only present when the DNA is damaged. It influences the damaged chromatin through a derepression on a gene promoter. Consequently this protein is quite interesting for biotechnical applications. Indeed, developing proteins who repair DNA damage is a meaningful goal in research especially in new cancer therapies.

== Structure ==

=== Structural highlights ===

This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.

This protein has four principal domains: a A-domain, a catalytic domain and two substrate binding domains[https://www.uniprot.org/uniprot/Q86W56].
The first 456 amino acids of the peptide chain form the A-domain. Then from 610 to 795 amino acids is located the catalytic domain. This catalytic domain can binding with other proteins with two amino acids (the 726 and 727 amino acids). Next the second substrate binding domain is located from the 869 th to the 874th amino acids.
So, most of the amino acids form the A-domain and the catzlytic domain and only few amino acids (8 a.a) make links with other proteins.

=== Quaternary Structure ===

Poly(ADP-ribose)glycohydrolase interact with PCNA or NUDT5. When this protein is binding with NUDT5 it can remodeling chromatin.[https://www.uniprot.org/uniprot/Q86W56]

=== Links of PARG with other ligands ===

== Function ==
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.
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 ligand (of identification number on PDB: 7JB) that can bind to the PARG creating the protein complex 6HMM.
=== Post-translational modifications and anthraquinone===
There are several possible post-translational modifications to stabilize DNA. Most commonly they 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, now repaired, site 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>.

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."/>.

=== The mechanism ===
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 then 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."/>. 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>.

== Diseases and Relevance ==

</StructureSection>
== References ==
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