4dcd - Revision history

OCA at 09:55, 30 October 2024

2024-10-30T09:55:36Z

← Older revision		Revision as of 09:55, 30 October 2024
Line 10:		Line 10:
	== Function ==		== Function ==
	[https://www.uniprot.org/uniprot/POLG_POL1M POLG_POL1M] Capsid proteins VP1, VP2, VP3 and VP4 form a closed capsid enclosing the viral positive strand RNA genome. VP4 lies on the inner surface of the protein shell formed by VP1, VP2 and VP3. All the three latter proteins contain a beta-sheet structure called beta-barrel jelly roll. Together they form an icosahedral capsid (T=3) composed of 60 copies of each VP1, VP2, and VP3, with a diameter of approximately 300 Angstroms. VP1 is situated at the 12 fivefold axes, whereas VP2 and VP3 are located at the quasi-sixfold axes. The interaction of five VP1 proteins in the fivefold axes results in a prominent protusion extending to about 25 Angstroms from the capsid shell. The resulting structure appears as a steep plateau encircled by a valley or cleft. This depression also termed canyon is the receptor binding site. The capsid interacts with human PVR at this site to provide virion attachment to target cell. This attachment induces virion internalization predominantly through clathrin- and caveolin-independent endocytosis in Hela cells and through caveolin-mediated endocytosis in brain microvascular endothelial cells. VP4 and VP1 subsequently undergo conformational changes leading to the formation of a pore in the endosomal membrane, thereby delivering the viral genome into the cytoplasm.<ref>PMID:9755863</ref> <ref>PMID:15919927</ref> <ref>PMID:18191571</ref> VP0 precursor is a component of immature procapsids (By similarity).<ref>PMID:9755863</ref> <ref>PMID:15919927</ref> <ref>PMID:18191571</ref> Protein 2A is a cysteine protease that is responsible for the cleavage between the P1 and P2 regions. It cleaves the host translation initiation factor EIF4G1, in order to shut down the capped cellular mRNA transcription.<ref>PMID:9755863</ref> <ref>PMID:15919927</ref> <ref>PMID:18191571</ref> Protein 2B affects membrane integrity and cause an increase in membrane permeability (By similarity).<ref>PMID:9755863</ref> <ref>PMID:15919927</ref> <ref>PMID:18191571</ref> Protein 2C associates with and induces structural rearrangements of intracellular membranes. It displays RNA-binding, nucleotide binding and NTPase activities.<ref>PMID:9755863</ref> <ref>PMID:15919927</ref> <ref>PMID:18191571</ref> Protein 3A, via its hydrophobic domain, serves as membrane anchor. It also inhibits endoplasmic reticulum-to-Golgi transport (By similarity).<ref>PMID:9755863</ref> <ref>PMID:15919927</ref> <ref>PMID:18191571</ref> Protein 3C is a cysteine protease that generates mature viral proteins from the precursor polyprotein. In addition to its proteolytic activity, it binds to viral RNA, and thus influences viral genome replication. RNA and substrate bind co-operatively to the protease (By similarity).<ref>PMID:9755863</ref> <ref>PMID:15919927</ref> <ref>PMID:18191571</ref> RNA-directed RNA polymerase 3D-POL replicates genomic and antigenomic RNA by recognizing replications specific signals (By similarity).<ref>PMID:9755863</ref> <ref>PMID:15919927</ref> <ref>PMID:18191571</ref>		[https://www.uniprot.org/uniprot/POLG_POL1M POLG_POL1M] Capsid proteins VP1, VP2, VP3 and VP4 form a closed capsid enclosing the viral positive strand RNA genome. VP4 lies on the inner surface of the protein shell formed by VP1, VP2 and VP3. All the three latter proteins contain a beta-sheet structure called beta-barrel jelly roll. Together they form an icosahedral capsid (T=3) composed of 60 copies of each VP1, VP2, and VP3, with a diameter of approximately 300 Angstroms. VP1 is situated at the 12 fivefold axes, whereas VP2 and VP3 are located at the quasi-sixfold axes. The interaction of five VP1 proteins in the fivefold axes results in a prominent protusion extending to about 25 Angstroms from the capsid shell. The resulting structure appears as a steep plateau encircled by a valley or cleft. This depression also termed canyon is the receptor binding site. The capsid interacts with human PVR at this site to provide virion attachment to target cell. This attachment induces virion internalization predominantly through clathrin- and caveolin-independent endocytosis in Hela cells and through caveolin-mediated endocytosis in brain microvascular endothelial cells. VP4 and VP1 subsequently undergo conformational changes leading to the formation of a pore in the endosomal membrane, thereby delivering the viral genome into the cytoplasm.<ref>PMID:9755863</ref> <ref>PMID:15919927</ref> <ref>PMID:18191571</ref> VP0 precursor is a component of immature procapsids (By similarity).<ref>PMID:9755863</ref> <ref>PMID:15919927</ref> <ref>PMID:18191571</ref> Protein 2A is a cysteine protease that is responsible for the cleavage between the P1 and P2 regions. It cleaves the host translation initiation factor EIF4G1, in order to shut down the capped cellular mRNA transcription.<ref>PMID:9755863</ref> <ref>PMID:15919927</ref> <ref>PMID:18191571</ref> Protein 2B affects membrane integrity and cause an increase in membrane permeability (By similarity).<ref>PMID:9755863</ref> <ref>PMID:15919927</ref> <ref>PMID:18191571</ref> Protein 2C associates with and induces structural rearrangements of intracellular membranes. It displays RNA-binding, nucleotide binding and NTPase activities.<ref>PMID:9755863</ref> <ref>PMID:15919927</ref> <ref>PMID:18191571</ref> Protein 3A, via its hydrophobic domain, serves as membrane anchor. It also inhibits endoplasmic reticulum-to-Golgi transport (By similarity).<ref>PMID:9755863</ref> <ref>PMID:15919927</ref> <ref>PMID:18191571</ref> Protein 3C is a cysteine protease that generates mature viral proteins from the precursor polyprotein. In addition to its proteolytic activity, it binds to viral RNA, and thus influences viral genome replication. RNA and substrate bind co-operatively to the protease (By similarity).<ref>PMID:9755863</ref> <ref>PMID:15919927</ref> <ref>PMID:18191571</ref> RNA-directed RNA polymerase 3D-POL replicates genomic and antigenomic RNA by recognizing replications specific signals (By similarity).<ref>PMID:9755863</ref> <ref>PMID:15919927</ref> <ref>PMID:18191571</ref>
			<div style="background-color:#fffaf0;">
			== Publication Abstract from PubMed ==
			Phylogenetic analysis has demonstrated that some positive sense RNA viruses can be classified into the picornavirus-like supercluster, which includes picornaviruses, caliciviruses and coronaviruses. These viruses possess 3C or 3C-like proteases (3Cpro or 3CLpro, respectively) which contain a typical chymotrypsin-like fold and a catalytic triad (or dyad) with a Cys residue as a nucleophile. The conserved key sites of 3Cpro or 3CLpro may serve as an attractive target for the design of broad-spectrum antivirals for multiple viruses in the supercluster. We have previously reported the structure-based design and synthesis of potent protease inhibitors of Norwalk virus (NV), a member of the Caliciviridae family. We report herein the broad-spectrum antiviral activities of three compounds possessing a common dipeptidyl residue with different warheads, aldehyde (GC373), bisulfite adduct (GC376) and alpha-ketoamide (GC375), against viruses that belong to the supercluster. All compounds were highly effective against the majority of tested viruses with the half maximal inhibitory concentration in the high nanomolar or low micromolar range in the enzyme and/or cell-based assays with high therapeutic indices. We also report the high-resolution X-ray cocrystal structures of the NV 3CLpro-, poliovirus 3Cpro- or transmissible gastroenteritis virus 3CLpro-inhibitor GC376 complex that show the compound covalently bound to a nucleophilic Cys residue in the catalytic site of the corresponding protease. We conclude that these compounds have the potential to be developed as antiviral therapeutics aimed at a single virus or multiple viruses in the picornavirus-like supercluster by targeting 3Cpro or 3CLpro.

			Broad-Spectrum Antivirals against 3C or 3C-like Proteases of Picornaviruses, Noroviruses and Coronaviruses.,Kim Y, Lovell S, Tiew KC, Mandadapu SR, Alliston KR, Battaile KP, Groutas WC, Chang KO J Virol. 2012 Aug 22. PMID:22915796<ref>PMID:22915796</ref>

			From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
			</div>
			<div class="pdbe-citations 4dcd" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==
	*[[RNA-directed RNA polymerase\|RNA-directed RNA polymerase]]		*[[RNA-directed RNA polymerase\|RNA-directed RNA polymerase]]
			*[[Virus protease 3D structures\|Virus protease 3D structures]]
	== References ==		== References ==
	<references/>		<references/>

OCA at 14:31, 14 March 2024

2024-03-14T14:31:22Z

← Older revision		Revision as of 14:31, 14 March 2024
Line 4:		Line 4:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4dcd]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human_poliovirus_1_Mahoney Human poliovirus 1 Mahoney]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4DCD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4DCD FirstGlance]. <br>		<table><tr><td colspan='2'>[[4dcd]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human_poliovirus_1_Mahoney Human poliovirus 1 Mahoney]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4DCD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4DCD FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DTT:2,3-DIHYDROXY-1,4-DITHIOBUTANE'>DTT</scene>, <scene name='pdbligand=K36:(1S,2S)-2-({N-[(BENZYLOXY)CARBONYL]-L-LEUCYL}AMINO)-1-HYDROXY-3-[(3S)-2-OXOPYRROLIDIN-3-YL]PROPANE-1-SULFONIC+ACID'>K36</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>		</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution\|Resolution]] 1.69Å</td></tr>
			<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DTT:2,3-DIHYDROXY-1,4-DITHIOBUTANE'>DTT</scene>, <scene name='pdbligand=K36:(1S,2S)-2-({N-[(BENZYLOXY)CARBONYL]-L-LEUCYL}AMINO)-1-HYDROXY-3-[(3S)-2-OXOPYRROLIDIN-3-YL]PROPANE-1-SULFONIC+ACID'>K36</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4dcd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dcd OCA], [https://pdbe.org/4dcd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4dcd RCSB], [https://www.ebi.ac.uk/pdbsum/4dcd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4dcd ProSAT]</span></td></tr>		<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4dcd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dcd OCA], [https://pdbe.org/4dcd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4dcd RCSB], [https://www.ebi.ac.uk/pdbsum/4dcd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4dcd ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
	[[https://www.uniprot.org/uniprot/POLG_POL1M POLG_POL1M]] Capsid proteins VP1, VP2, VP3 and VP4 form a closed capsid enclosing the viral positive strand RNA genome. VP4 lies on the inner surface of the protein shell formed by VP1, VP2 and VP3. All the three latter proteins contain a beta-sheet structure called beta-barrel jelly roll. Together they form an icosahedral capsid (T=3) composed of 60 copies of each VP1, VP2, and VP3, with a diameter of approximately 300 Angstroms. VP1 is situated at the 12 fivefold axes, whereas VP2 and VP3 are located at the quasi-sixfold axes. The interaction of five VP1 proteins in the fivefold axes results in a prominent protusion extending to about 25 Angstroms from the capsid shell. The resulting structure appears as a steep plateau encircled by a valley or cleft. This depression also termed canyon is the receptor binding site. The capsid interacts with human PVR at this site to provide virion attachment to target cell. This attachment induces virion internalization predominantly through clathrin- and caveolin-independent endocytosis in Hela cells and through caveolin-mediated endocytosis in brain microvascular endothelial cells. VP4 and VP1 subsequently undergo conformational changes leading to the formation of a pore in the endosomal membrane, thereby delivering the viral genome into the cytoplasm.<ref>PMID:9755863</ref> <ref>PMID:15919927</ref> <ref>PMID:18191571</ref> VP0 precursor is a component of immature procapsids (By similarity).<ref>PMID:9755863</ref> <ref>PMID:15919927</ref> <ref>PMID:18191571</ref> Protein 2A is a cysteine protease that is responsible for the cleavage between the P1 and P2 regions. It cleaves the host translation initiation factor EIF4G1, in order to shut down the capped cellular mRNA transcription.<ref>PMID:9755863</ref> <ref>PMID:15919927</ref> <ref>PMID:18191571</ref> Protein 2B affects membrane integrity and cause an increase in membrane permeability (By similarity).<ref>PMID:9755863</ref> <ref>PMID:15919927</ref> <ref>PMID:18191571</ref> Protein 2C associates with and induces structural rearrangements of intracellular membranes. It displays RNA-binding, nucleotide binding and NTPase activities.<ref>PMID:9755863</ref> <ref>PMID:15919927</ref> <ref>PMID:18191571</ref> Protein 3A, via its hydrophobic domain, serves as membrane anchor. It also inhibits endoplasmic reticulum-to-Golgi transport (By similarity).<ref>PMID:9755863</ref> <ref>PMID:15919927</ref> <ref>PMID:18191571</ref> Protein 3C is a cysteine protease that generates mature viral proteins from the precursor polyprotein. In addition to its proteolytic activity, it binds to viral RNA, and thus influences viral genome replication. RNA and substrate bind co-operatively to the protease (By similarity).<ref>PMID:9755863</ref> <ref>PMID:15919927</ref> <ref>PMID:18191571</ref> RNA-directed RNA polymerase 3D-POL replicates genomic and antigenomic RNA by recognizing replications specific signals (By similarity).<ref>PMID:9755863</ref> <ref>PMID:15919927</ref> <ref>PMID:18191571</ref>		[https://www.uniprot.org/uniprot/POLG_POL1M POLG_POL1M] Capsid proteins VP1, VP2, VP3 and VP4 form a closed capsid enclosing the viral positive strand RNA genome. VP4 lies on the inner surface of the protein shell formed by VP1, VP2 and VP3. All the three latter proteins contain a beta-sheet structure called beta-barrel jelly roll. Together they form an icosahedral capsid (T=3) composed of 60 copies of each VP1, VP2, and VP3, with a diameter of approximately 300 Angstroms. VP1 is situated at the 12 fivefold axes, whereas VP2 and VP3 are located at the quasi-sixfold axes. The interaction of five VP1 proteins in the fivefold axes results in a prominent protusion extending to about 25 Angstroms from the capsid shell. The resulting structure appears as a steep plateau encircled by a valley or cleft. This depression also termed canyon is the receptor binding site. The capsid interacts with human PVR at this site to provide virion attachment to target cell. This attachment induces virion internalization predominantly through clathrin- and caveolin-independent endocytosis in Hela cells and through caveolin-mediated endocytosis in brain microvascular endothelial cells. VP4 and VP1 subsequently undergo conformational changes leading to the formation of a pore in the endosomal membrane, thereby delivering the viral genome into the cytoplasm.<ref>PMID:9755863</ref> <ref>PMID:15919927</ref> <ref>PMID:18191571</ref> VP0 precursor is a component of immature procapsids (By similarity).<ref>PMID:9755863</ref> <ref>PMID:15919927</ref> <ref>PMID:18191571</ref> Protein 2A is a cysteine protease that is responsible for the cleavage between the P1 and P2 regions. It cleaves the host translation initiation factor EIF4G1, in order to shut down the capped cellular mRNA transcription.<ref>PMID:9755863</ref> <ref>PMID:15919927</ref> <ref>PMID:18191571</ref> Protein 2B affects membrane integrity and cause an increase in membrane permeability (By similarity).<ref>PMID:9755863</ref> <ref>PMID:15919927</ref> <ref>PMID:18191571</ref> Protein 2C associates with and induces structural rearrangements of intracellular membranes. It displays RNA-binding, nucleotide binding and NTPase activities.<ref>PMID:9755863</ref> <ref>PMID:15919927</ref> <ref>PMID:18191571</ref> Protein 3A, via its hydrophobic domain, serves as membrane anchor. It also inhibits endoplasmic reticulum-to-Golgi transport (By similarity).<ref>PMID:9755863</ref> <ref>PMID:15919927</ref> <ref>PMID:18191571</ref> Protein 3C is a cysteine protease that generates mature viral proteins from the precursor polyprotein. In addition to its proteolytic activity, it binds to viral RNA, and thus influences viral genome replication. RNA and substrate bind co-operatively to the protease (By similarity).<ref>PMID:9755863</ref> <ref>PMID:15919927</ref> <ref>PMID:18191571</ref> RNA-directed RNA polymerase 3D-POL replicates genomic and antigenomic RNA by recognizing replications specific signals (By similarity).<ref>PMID:9755863</ref> <ref>PMID:15919927</ref> <ref>PMID:18191571</ref>
	~~<div style="background-color:#fffaf0;">~~
	~~== Publication Abstract from PubMed ==~~
	Phylogenetic analysis has demonstrated that some positive sense RNA viruses can be classified into the picornavirus-like supercluster, which includes picornaviruses, caliciviruses and coronaviruses. These viruses possess 3C or 3C-like proteases (3Cpro or 3CLpro, respectively) which contain a typical chymotrypsin-like fold and a catalytic triad (or dyad) with a Cys residue as a nucleophile. The conserved key sites of 3Cpro or 3CLpro may serve as an attractive target for the design of broad-spectrum antivirals for multiple viruses in the supercluster. We have previously reported the structure-based design and synthesis of potent protease inhibitors of Norwalk virus (NV), a member of the Caliciviridae family. We report herein the broad-spectrum antiviral activities of three compounds possessing a common dipeptidyl residue with different warheads, aldehyde (GC373), bisulfite adduct (GC376) and alpha-ketoamide (GC375), against viruses that belong to the supercluster. All compounds were highly effective against the majority of tested viruses with the half maximal inhibitory concentration in the high nanomolar or low micromolar range in the enzyme and/or cell-based assays with high therapeutic indices. We also report the high-resolution X-ray cocrystal structures of the NV 3CLpro-, poliovirus 3Cpro- or transmissible gastroenteritis virus 3CLpro-inhibitor GC376 complex that show the compound covalently bound to a nucleophilic Cys residue in the catalytic site of the corresponding protease. We conclude that these compounds have the potential to be developed as antiviral therapeutics aimed at a single virus or multiple viruses in the picornavirus-like supercluster by targeting 3Cpro or 3CLpro.

	Broad-Spectrum Antivirals against 3C or 3C-like Proteases of Picornaviruses, Noroviruses and Coronaviruses.,Kim Y, Lovell S, Tiew KC, Mandadapu SR, Alliston KR, Battaile KP, Groutas WC, Chang KO J Virol. 2012 Aug 22. PMID:22915796<ref>PMID:22915796</ref>

	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~
	~~</div>~~
	~~<div class="pdbe-citations 4dcd" style="background-color:#fffaf0;"></div~~>

	==See Also==		==See Also==

OCA at 08:11, 21 September 2022

2022-09-21T08:11:26Z

← Older revision		Revision as of 08:11, 21 September 2022
Line 3:		Line 3:
	<StructureSection load='4dcd' size='340' side='right'caption='[[4dcd]], [[Resolution\|resolution]] 1.69Å' scene=''>		<StructureSection load='4dcd' size='340' side='right'caption='[[4dcd]], [[Resolution\|resolution]] 1.69Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4dcd]] is a 1 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/~~Human_poliovirus_1_mahoney~~ Human poliovirus 1 ~~mahoney~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4DCD OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://proteopedia.org/fgij/fg.htm?mol=4DCD FirstGlance]. <br>		<table><tr><td colspan='2'>[[4dcd]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human_poliovirus_1_Mahoney Human poliovirus 1 Mahoney]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4DCD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4DCD FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DTT:2,3-DIHYDROXY-1,4-DITHIOBUTANE'>DTT</scene>, <scene name='pdbligand=K36:(1S,2S)-2-({N-[(BENZYLOXY)CARBONYL]-L-LEUCYL}AMINO)-1-HYDROXY-3-[(3S)-2-OXOPYRROLIDIN-3-YL]PROPANE-1-SULFONIC+ACID'>K36</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DTT:2,3-DIHYDROXY-1,4-DITHIOBUTANE'>DTT</scene>, <scene name='pdbligand=K36:(1S,2S)-2-({N-[(BENZYLOXY)CARBONYL]-L-LEUCYL}AMINO)-1-HYDROXY-3-[(3S)-2-OXOPYRROLIDIN-3-YL]PROPANE-1-SULFONIC+ACID'>K36</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
	~~<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3ur9\|3ur9]], [[4f49\|4f49]], [[3ur6\|3ur6]]</td></tr>~~		<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4dcd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dcd OCA], [https://pdbe.org/4dcd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4dcd RCSB], [https://www.ebi.ac.uk/pdbsum/4dcd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4dcd ProSAT]</span></td></tr>
	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Picornain_3C Picornain 3C], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.22.28 3.4.22.28] </span></td></tr>
	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[~~http~~://proteopedia.org/fgij/fg.htm?mol=4dcd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dcd OCA], [~~http~~://pdbe.org/4dcd PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=4dcd RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/4dcd PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=4dcd ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
	[[~~http~~://www.uniprot.org/uniprot/POLG_POL1M POLG_POL1M]] Capsid proteins VP1, VP2, VP3 and VP4 form a closed capsid enclosing the viral positive strand RNA genome. VP4 lies on the inner surface of the protein shell formed by VP1, VP2 and VP3. All the three latter proteins contain a beta-sheet structure called beta-barrel jelly roll. Together they form an icosahedral capsid (T=3) composed of 60 copies of each VP1, VP2, and VP3, with a diameter of approximately 300 Angstroms. VP1 is situated at the 12 fivefold axes, whereas VP2 and VP3 are located at the quasi-sixfold axes. The interaction of five VP1 proteins in the fivefold axes results in a prominent protusion extending to about 25 Angstroms from the capsid shell. The resulting structure appears as a steep plateau encircled by a valley or cleft. This depression also termed canyon is the receptor binding site. The capsid interacts with human PVR at this site to provide virion attachment to target cell. This attachment induces virion internalization predominantly through clathrin- and caveolin-independent endocytosis in Hela cells and through caveolin-mediated endocytosis in brain microvascular endothelial cells. VP4 and VP1 subsequently undergo conformational changes leading to the formation of a pore in the endosomal membrane, thereby delivering the viral genome into the cytoplasm.<ref>PMID:9755863</ref> <ref>PMID:15919927</ref> <ref>PMID:18191571</ref> VP0 precursor is a component of immature procapsids (By similarity).<ref>PMID:9755863</ref> <ref>PMID:15919927</ref> <ref>PMID:18191571</ref> Protein 2A is a cysteine protease that is responsible for the cleavage between the P1 and P2 regions. It cleaves the host translation initiation factor EIF4G1, in order to shut down the capped cellular mRNA transcription.<ref>PMID:9755863</ref> <ref>PMID:15919927</ref> <ref>PMID:18191571</ref> Protein 2B affects membrane integrity and cause an increase in membrane permeability (By similarity).<ref>PMID:9755863</ref> <ref>PMID:15919927</ref> <ref>PMID:18191571</ref> Protein 2C associates with and induces structural rearrangements of intracellular membranes. It displays RNA-binding, nucleotide binding and NTPase activities.<ref>PMID:9755863</ref> <ref>PMID:15919927</ref> <ref>PMID:18191571</ref> Protein 3A, via its hydrophobic domain, serves as membrane anchor. It also inhibits endoplasmic reticulum-to-Golgi transport (By similarity).<ref>PMID:9755863</ref> <ref>PMID:15919927</ref> <ref>PMID:18191571</ref> Protein 3C is a cysteine protease that generates mature viral proteins from the precursor polyprotein. In addition to its proteolytic activity, it binds to viral RNA, and thus influences viral genome replication. RNA and substrate bind co-operatively to the protease (By similarity).<ref>PMID:9755863</ref> <ref>PMID:15919927</ref> <ref>PMID:18191571</ref> RNA-directed RNA polymerase 3D-POL replicates genomic and antigenomic RNA by recognizing replications specific signals (By similarity).<ref>PMID:9755863</ref> <ref>PMID:15919927</ref> <ref>PMID:18191571</ref>		[[https://www.uniprot.org/uniprot/POLG_POL1M POLG_POL1M]] Capsid proteins VP1, VP2, VP3 and VP4 form a closed capsid enclosing the viral positive strand RNA genome. VP4 lies on the inner surface of the protein shell formed by VP1, VP2 and VP3. All the three latter proteins contain a beta-sheet structure called beta-barrel jelly roll. Together they form an icosahedral capsid (T=3) composed of 60 copies of each VP1, VP2, and VP3, with a diameter of approximately 300 Angstroms. VP1 is situated at the 12 fivefold axes, whereas VP2 and VP3 are located at the quasi-sixfold axes. The interaction of five VP1 proteins in the fivefold axes results in a prominent protusion extending to about 25 Angstroms from the capsid shell. The resulting structure appears as a steep plateau encircled by a valley or cleft. This depression also termed canyon is the receptor binding site. The capsid interacts with human PVR at this site to provide virion attachment to target cell. This attachment induces virion internalization predominantly through clathrin- and caveolin-independent endocytosis in Hela cells and through caveolin-mediated endocytosis in brain microvascular endothelial cells. VP4 and VP1 subsequently undergo conformational changes leading to the formation of a pore in the endosomal membrane, thereby delivering the viral genome into the cytoplasm.<ref>PMID:9755863</ref> <ref>PMID:15919927</ref> <ref>PMID:18191571</ref> VP0 precursor is a component of immature procapsids (By similarity).<ref>PMID:9755863</ref> <ref>PMID:15919927</ref> <ref>PMID:18191571</ref> Protein 2A is a cysteine protease that is responsible for the cleavage between the P1 and P2 regions. It cleaves the host translation initiation factor EIF4G1, in order to shut down the capped cellular mRNA transcription.<ref>PMID:9755863</ref> <ref>PMID:15919927</ref> <ref>PMID:18191571</ref> Protein 2B affects membrane integrity and cause an increase in membrane permeability (By similarity).<ref>PMID:9755863</ref> <ref>PMID:15919927</ref> <ref>PMID:18191571</ref> Protein 2C associates with and induces structural rearrangements of intracellular membranes. It displays RNA-binding, nucleotide binding and NTPase activities.<ref>PMID:9755863</ref> <ref>PMID:15919927</ref> <ref>PMID:18191571</ref> Protein 3A, via its hydrophobic domain, serves as membrane anchor. It also inhibits endoplasmic reticulum-to-Golgi transport (By similarity).<ref>PMID:9755863</ref> <ref>PMID:15919927</ref> <ref>PMID:18191571</ref> Protein 3C is a cysteine protease that generates mature viral proteins from the precursor polyprotein. In addition to its proteolytic activity, it binds to viral RNA, and thus influences viral genome replication. RNA and substrate bind co-operatively to the protease (By similarity).<ref>PMID:9755863</ref> <ref>PMID:15919927</ref> <ref>PMID:18191571</ref> RNA-directed RNA polymerase 3D-POL replicates genomic and antigenomic RNA by recognizing replications specific signals (By similarity).<ref>PMID:9755863</ref> <ref>PMID:15919927</ref> <ref>PMID:18191571</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 27:		Line 25:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
	[[Category: Human poliovirus 1 ~~mahoney~~]]		[[Category: Human poliovirus 1 Mahoney]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
	~~[[Category: Picornain 3C]]~~		[[Category: Alliston KR]]
	[[Category: Alliston~~, K R~~]]		[[Category: Battaile KP]]
	[[Category: Battaile~~, K P~~]]		[[Category: Chang KO]]
	[[Category: Chang~~, K O~~]]		[[Category: Groutas WC]]
	[[Category: Groutas~~, W C~~]]		[[Category: Kim Y]]
	[[Category: Kim, Y]]		[[Category: Lovell S]]
	[[Category: Lovell, S]]		[[Category: Mandadapu SR]]
	[[Category: Mandadapu~~, S R~~]]		[[Category: Tiew K-C]]
	[[Category: Tiew, K C]]
	~~[[Category: Antiviral inhibitor]]~~
	~~[[Category: Dipeptidyl inhibitor]]~~
	~~[[Category: Hydrolase-hydrolase inhibitor complex]]~~
	~~[[Category: Poliovirus]]~~
	~~[[Category: Protease~~]]

OCA at 05:54, 20 May 2020

2020-05-20T05:54:31Z

← Older revision		Revision as of 05:54, 20 May 2020
Line 3:		Line 3:
	<StructureSection load='4dcd' size='340' side='right'caption='[[4dcd]], [[Resolution\|resolution]] 1.69Å' scene=''>		<StructureSection load='4dcd' size='340' side='right'caption='[[4dcd]], [[Resolution\|resolution]] 1.69Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4dcd]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human_poliovirus_1_mahoney Human poliovirus 1 mahoney]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4DCD OCA]. For a <b>guided tour on the structure components</b> use [http://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4DCD FirstGlance]. <br>		<table><tr><td colspan='2'>[[4dcd]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human_poliovirus_1_mahoney Human poliovirus 1 mahoney]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4DCD OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=4DCD FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DTT:2,3-DIHYDROXY-1,4-DITHIOBUTANE'>DTT</scene>, <scene name='pdbligand=K36:(1S,2S)-2-({N-[(BENZYLOXY)CARBONYL]-L-LEUCYL}AMINO)-1-HYDROXY-3-[(3S)-2-OXOPYRROLIDIN-3-YL]PROPANE-1-SULFONIC+ACID'>K36</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DTT:2,3-DIHYDROXY-1,4-DITHIOBUTANE'>DTT</scene>, <scene name='pdbligand=K36:(1S,2S)-2-({N-[(BENZYLOXY)CARBONYL]-L-LEUCYL}AMINO)-1-HYDROXY-3-[(3S)-2-OXOPYRROLIDIN-3-YL]PROPANE-1-SULFONIC+ACID'>K36</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3ur9\|3ur9]], [[4f49\|4f49]], [[3ur6\|3ur6]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3ur9\|3ur9]], [[4f49\|4f49]], [[3ur6\|3ur6]]</td></tr>
	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Picornain_3C Picornain 3C], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.22.28 3.4.22.28] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Picornain_3C Picornain 3C], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.22.28 3.4.22.28] </span></td></tr>
	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4dcd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dcd OCA], [http://pdbe.org/4dcd PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4dcd RCSB], [http://www.ebi.ac.uk/pdbsum/4dcd PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4dcd ProSAT]</span></td></tr>		<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=4dcd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dcd OCA], [http://pdbe.org/4dcd PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4dcd RCSB], [http://www.ebi.ac.uk/pdbsum/4dcd PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4dcd ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==

OCA at 16:27, 28 August 2019

2019-08-28T16:27:11Z

← Older revision		Revision as of 16:27, 28 August 2019
Line 1:		Line 1:

	==1.6A resolution structure of PolioVirus 3C Protease Containing a covalently bound dipeptidyl inhibitor==		==1.6A resolution structure of PolioVirus 3C Protease Containing a covalently bound dipeptidyl inhibitor==
	<StructureSection load='4dcd' size='340' side='right' caption='[[4dcd]], [[Resolution\|resolution]] 1.69Å' scene=''>		<StructureSection load='4dcd' size='340' side='right'caption='[[4dcd]], [[Resolution\|resolution]] 1.69Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4dcd]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human_poliovirus_1_mahoney Human poliovirus 1 mahoney]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4DCD OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4DCD FirstGlance]. <br>		<table><tr><td colspan='2'>[[4dcd]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human_poliovirus_1_mahoney Human poliovirus 1 mahoney]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4DCD OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4DCD FirstGlance]. <br>
Line 20:		Line 20:
	</div>		</div>
	<div class="pdbe-citations 4dcd" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 4dcd" style="background-color:#fffaf0;"></div>

			==See Also==
			*[[RNA-directed RNA polymerase\|RNA-directed RNA polymerase]]
	== References ==		== References ==
	<references/>		<references/>
Line 25:		Line 28:
	</StructureSection>		</StructureSection>
	[[Category: Human poliovirus 1 mahoney]]		[[Category: Human poliovirus 1 mahoney]]
			[[Category: Large Structures]]
	[[Category: Picornain 3C]]		[[Category: Picornain 3C]]
	[[Category: Alliston, K R]]		[[Category: Alliston, K R]]

OCA at 07:51, 15 November 2017

2017-11-15T07:51:36Z

← Older revision		Revision as of 07:51, 15 November 2017
Line 20:		Line 20:
	</div>		</div>
	<div class="pdbe-citations 4dcd" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 4dcd" style="background-color:#fffaf0;"></div>

	~~==See Also==~~
	*[[RNA-directed RNA polymerase\|RNA-directed RNA polymerase]]
	== References ==		== References ==
	<references/>		<references/>

OCA at 13:19, 5 August 2016

2016-08-05T13:19:06Z

← Older revision		Revision as of 13:19, 5 August 2016
Line 1:		Line 1:

	==1.6A resolution structure of PolioVirus 3C Protease Containing a covalently bound dipeptidyl inhibitor==		==1.6A resolution structure of PolioVirus 3C Protease Containing a covalently bound dipeptidyl inhibitor==
	<StructureSection load='4dcd' size='340' side='right' caption='[[4dcd]], [[Resolution\|resolution]] 1.69Å' scene=''>		<StructureSection load='4dcd' size='340' side='right' caption='[[4dcd]], [[Resolution\|resolution]] 1.69Å' scene=''>
Line 6:		Line 7:
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3ur9\|3ur9]], [[4f49\|4f49]], [[3ur6\|3ur6]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3ur9\|3ur9]], [[4f49\|4f49]], [[3ur6\|3ur6]]</td></tr>
	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Picornain_3C Picornain 3C], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.22.28 3.4.22.28] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Picornain_3C Picornain 3C], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.22.28 3.4.22.28] </span></td></tr>
	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4dcd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dcd OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4dcd RCSB], [http://www.ebi.ac.uk/pdbsum/4dcd PDBsum]</span></td></tr>		<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4dcd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dcd OCA], [http://pdbe.org/4dcd PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4dcd RCSB], [http://www.ebi.ac.uk/pdbsum/4dcd PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4dcd ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
Line 18:		Line 19:
	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
	</div>		</div>
			<div class="pdbe-citations 4dcd" style="background-color:#fffaf0;"></div>

			==See Also==
			*[[RNA-directed RNA polymerase\|RNA-directed RNA polymerase]]
	== References ==		== References ==
	<references/>		<references/>

OCA at 19:09, 25 December 2014

2014-12-25T19:09:04Z

← Older revision		Revision as of 19:09, 25 December 2014
Line 8:		Line 8:
	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4dcd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dcd OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4dcd RCSB], [http://www.ebi.ac.uk/pdbsum/4dcd PDBsum]</span></td></tr>		<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4dcd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dcd OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4dcd RCSB], [http://www.ebi.ac.uk/pdbsum/4dcd PDBsum]</span></td></tr>
	</table>		</table>
			== Function ==
			[[http://www.uniprot.org/uniprot/POLG_POL1M POLG_POL1M]] Capsid proteins VP1, VP2, VP3 and VP4 form a closed capsid enclosing the viral positive strand RNA genome. VP4 lies on the inner surface of the protein shell formed by VP1, VP2 and VP3. All the three latter proteins contain a beta-sheet structure called beta-barrel jelly roll. Together they form an icosahedral capsid (T=3) composed of 60 copies of each VP1, VP2, and VP3, with a diameter of approximately 300 Angstroms. VP1 is situated at the 12 fivefold axes, whereas VP2 and VP3 are located at the quasi-sixfold axes. The interaction of five VP1 proteins in the fivefold axes results in a prominent protusion extending to about 25 Angstroms from the capsid shell. The resulting structure appears as a steep plateau encircled by a valley or cleft. This depression also termed canyon is the receptor binding site. The capsid interacts with human PVR at this site to provide virion attachment to target cell. This attachment induces virion internalization predominantly through clathrin- and caveolin-independent endocytosis in Hela cells and through caveolin-mediated endocytosis in brain microvascular endothelial cells. VP4 and VP1 subsequently undergo conformational changes leading to the formation of a pore in the endosomal membrane, thereby delivering the viral genome into the cytoplasm.<ref>PMID:9755863</ref> <ref>PMID:15919927</ref> <ref>PMID:18191571</ref> VP0 precursor is a component of immature procapsids (By similarity).<ref>PMID:9755863</ref> <ref>PMID:15919927</ref> <ref>PMID:18191571</ref> Protein 2A is a cysteine protease that is responsible for the cleavage between the P1 and P2 regions. It cleaves the host translation initiation factor EIF4G1, in order to shut down the capped cellular mRNA transcription.<ref>PMID:9755863</ref> <ref>PMID:15919927</ref> <ref>PMID:18191571</ref> Protein 2B affects membrane integrity and cause an increase in membrane permeability (By similarity).<ref>PMID:9755863</ref> <ref>PMID:15919927</ref> <ref>PMID:18191571</ref> Protein 2C associates with and induces structural rearrangements of intracellular membranes. It displays RNA-binding, nucleotide binding and NTPase activities.<ref>PMID:9755863</ref> <ref>PMID:15919927</ref> <ref>PMID:18191571</ref> Protein 3A, via its hydrophobic domain, serves as membrane anchor. It also inhibits endoplasmic reticulum-to-Golgi transport (By similarity).<ref>PMID:9755863</ref> <ref>PMID:15919927</ref> <ref>PMID:18191571</ref> Protein 3C is a cysteine protease that generates mature viral proteins from the precursor polyprotein. In addition to its proteolytic activity, it binds to viral RNA, and thus influences viral genome replication. RNA and substrate bind co-operatively to the protease (By similarity).<ref>PMID:9755863</ref> <ref>PMID:15919927</ref> <ref>PMID:18191571</ref> RNA-directed RNA polymerase 3D-POL replicates genomic and antigenomic RNA by recognizing replications specific signals (By similarity).<ref>PMID:9755863</ref> <ref>PMID:15919927</ref> <ref>PMID:18191571</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==

OCA at 15:00, 9 December 2014

2014-12-09T15:00:55Z

← Older revision		Revision as of 15:00, 9 December 2014
Line 1:		Line 1:
	[[~~Image~~:~~4dcd~~.~~png~~\|~~left~~\|~~200px~~]]		==1.6A resolution structure of PolioVirus 3C Protease Containing a covalently bound dipeptidyl inhibitor==
			<StructureSection load='4dcd' size='340' side='right' caption='[[4dcd]], [[Resolution\|resolution]] 1.69Å' scene=''>
			== Structural highlights ==
			<table><tr><td colspan='2'>[[4dcd]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human_poliovirus_1_mahoney Human poliovirus 1 mahoney]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4DCD OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4DCD FirstGlance]. <br>
			</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DTT:2,3-DIHYDROXY-1,4-DITHIOBUTANE'>DTT</scene>, <scene name='pdbligand=K36:(1S,2S)-2-({N-[(BENZYLOXY)CARBONYL]-L-LEUCYL}AMINO)-1-HYDROXY-3-[(3S)-2-OXOPYRROLIDIN-3-YL]PROPANE-1-SULFONIC+ACID'>K36</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
			<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3ur9\|3ur9]], [[4f49\|4f49]], [[3ur6\|3ur6]]</td></tr>
			<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Picornain_3C Picornain 3C], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.22.28 3.4.22.28] </span></td></tr>
			<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4dcd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dcd OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4dcd RCSB], [http://www.ebi.ac.uk/pdbsum/4dcd PDBsum]</span></td></tr>
			</table>
			<div style="background-color:#fffaf0;">
			== Publication Abstract from PubMed ==
			Phylogenetic analysis has demonstrated that some positive sense RNA viruses can be classified into the picornavirus-like supercluster, which includes picornaviruses, caliciviruses and coronaviruses. These viruses possess 3C or 3C-like proteases (3Cpro or 3CLpro, respectively) which contain a typical chymotrypsin-like fold and a catalytic triad (or dyad) with a Cys residue as a nucleophile. The conserved key sites of 3Cpro or 3CLpro may serve as an attractive target for the design of broad-spectrum antivirals for multiple viruses in the supercluster. We have previously reported the structure-based design and synthesis of potent protease inhibitors of Norwalk virus (NV), a member of the Caliciviridae family. We report herein the broad-spectrum antiviral activities of three compounds possessing a common dipeptidyl residue with different warheads, aldehyde (GC373), bisulfite adduct (GC376) and alpha-ketoamide (GC375), against viruses that belong to the supercluster. All compounds were highly effective against the majority of tested viruses with the half maximal inhibitory concentration in the high nanomolar or low micromolar range in the enzyme and/or cell-based assays with high therapeutic indices. We also report the high-resolution X-ray cocrystal structures of the NV 3CLpro-, poliovirus 3Cpro- or transmissible gastroenteritis virus 3CLpro-inhibitor GC376 complex that show the compound covalently bound to a nucleophilic Cys residue in the catalytic site of the corresponding protease. We conclude that these compounds have the potential to be developed as antiviral therapeutics aimed at a single virus or multiple viruses in the picornavirus-like supercluster by targeting 3Cpro or 3CLpro.

	~~{{STRUCTURE_4dcd\| PDB=4dcd \| SCENE= }}~~		Broad-Spectrum Antivirals against 3C or 3C-like Proteases of Picornaviruses, Noroviruses and Coronaviruses.,Kim Y, Lovell S, Tiew KC, Mandadapu SR, Alliston KR, Battaile KP, Groutas WC, Chang KO J Virol. 2012 Aug 22. PMID:22915796<ref>PMID:22915796</ref>

	~~===1~~.~~6A resolution structure~~ of ~~PolioVirus 3C Protease Containing a covalently bound dipeptidyl inhibitor===~~		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
			</div>
			== References ==
	==~~About this Structure~~==		<references/>
	~~[[4dcd]] is a 1 chain structure with sequence from [http:~~//~~en.wikipedia.org/wiki/Human_poliovirus_1_mahoney Human poliovirus 1 mahoney]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4DCD OCA].~~		__TOC__
			</StructureSection>
	[[Category: Human poliovirus 1 mahoney]]		[[Category: Human poliovirus 1 mahoney]]
	[[Category: Picornain 3C]]		[[Category: Picornain 3C]]
	[[Category: Alliston, K R.]]		[[Category: Alliston, K R]]
	[[Category: Battaile, K P.]]		[[Category: Battaile, K P]]
	[[Category: Chang, K O.]]		[[Category: Chang, K O]]
	[[Category: Groutas, W C.]]		[[Category: Groutas, W C]]
	[[Category: Kim, Y.]]		[[Category: Kim, Y]]
	[[Category: Lovell, S.]]		[[Category: Lovell, S]]
	[[Category: Mandadapu, S R.]]		[[Category: Mandadapu, S R]]
	[[Category: Tiew, K C.]]		[[Category: Tiew, K C]]
	[[Category: Antiviral inhibitor]]		[[Category: Antiviral inhibitor]]
	[[Category: Dipeptidyl inhibitor]]		[[Category: Dipeptidyl inhibitor]]

OCA at 07:10, 14 November 2012

2012-11-14T07:10:33Z

← Older revision		Revision as of 07:10, 14 November 2012
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	[[Image:4dcd.~~jpg~~\|left\|200px]]		[[Image:4dcd.png\|left\|200px]]

	{{STRUCTURE_4dcd\| PDB=4dcd \| SCENE= }}		{{STRUCTURE_4dcd\| PDB=4dcd \| SCENE= }}
Line 5:		Line 5:
	===1.6A resolution structure of PolioVirus 3C Protease Containing a covalently bound dipeptidyl inhibitor===		===1.6A resolution structure of PolioVirus 3C Protease Containing a covalently bound dipeptidyl inhibitor===

	~~{{ABSTRACT_PUBMED_22915796}}~~

	==About this Structure==		==About this Structure==
	[[4dcd]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/~~Human_poliovirus_1~~ Human poliovirus 1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4DCD OCA].		[[4dcd]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human_poliovirus_1_mahoney Human poliovirus 1 mahoney]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4DCD OCA].
	[[Category: Human poliovirus 1]]		[[Category: Human poliovirus 1 mahoney]]
	[[Category: Picornain 3C]]		[[Category: Picornain 3C]]
	[[Category: Alliston, K R.]]		[[Category: Alliston, K R.]]