3sv9 - Revision history

OCA at 09:57, 1 March 2024

2024-03-01T09:57:37Z

←Older revision		Revision as of 09:57, 1 March 2024
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	<StructureSection load='3sv9' size='340' side='right'caption='[[3sv9]], [[Resolution\|resolution]] 1.60Å' scene=''>		<StructureSection load='3sv9' size='340' side='right'caption='[[3sv9]], [[Resolution\|resolution]] 1.60Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[3sv9]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/~~Hepatitis_c_virus_subtype_1a~~ Hepatitis c virus ~~subtype~~ 1a]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3SV9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3SV9 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[3sv9]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Hepatitis_C_virus_genotype_1a Hepatitis C virus genotype 1a]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3SV9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3SV9 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=SV6:(1S,3aR,6aS)-2-[(2S)-2-({(2S)-2-cyclohexyl-2-[(pyrazin-2-ylcarbonyl)amino]acetyl}amino)-3,3-dimethylbutanoyl]-N-[(2R,3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-yl]octahydrocyclopenta[c]pyrrole-1-carboxamide'>SV6</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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]] 1.6Å</td></tr>
-	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3su3\|3su3]], [[3su4\|3su4]], [[3su5\|3su5]], [[3su6\|3su6]], [[3sud\|3sud]], [[3sue\|3sue]], [[3suf\|3suf]], [[3sug\|3sug]], [[3sv6\|3sv6]], [[3sv7\|3sv7]], [[3sv8\|3sv8]]</div></td></tr>	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=SV6:(1S,3aR,6aS)-2-[(2S)-2-({(2S)-2-cyclohexyl-2-[(pyrazin-2-ylcarbonyl)amino]acetyl}amino)-3,3-dimethylbutanoyl]-N-[(2R,3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-yl]octahydrocyclopenta[c]pyrrole-1-carboxamide'>SV6</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
-	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">NS3-NS4A ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=31646 Hepatitis C virus subtype 1a])</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=3sv9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3sv9 OCA], [https://pdbe.org/3sv9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3sv9 RCSB], [https://www.ebi.ac.uk/pdbsum/3sv9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3sv9 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=3sv9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3sv9 OCA], [https://pdbe.org/3sv9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3sv9 RCSB], [https://www.ebi.ac.uk/pdbsum/3sv9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3sv9 ProSAT]</span></td></tr>
	</table>		</table>
-	~~<div style~~=~~"background-color:#fffaf0;">~~	+	== Function ==
-	=~~= Publication Abstract from PubMed~~ ==	+	[https://www.uniprot.org/uniprot/A8DG50_9HEPC A8DG50_9HEPC]
-	Hepatitis C virus (HCV) infects over 170 million people worldwide and is the leading cause of chronic liver diseases, including cirrhosis, liver failure, and liver cancer. Available antiviral therapies cause severe side effects and are effective only for a subset of patients, though treatment outcomes have recently been improved by the combination therapy now including boceprevir and telaprevir, which inhibit the viral NS3/4A protease. Despite extensive efforts to develop more potent next-generation protease inhibitors, however, the long-term efficacy of this drug class is challenged by the rapid emergence of resistance. Single-site mutations at protease residues R155, A156 and D168 confer resistance to nearly all inhibitors in clinical development. Thus, developing the next-generation of drugs that retain activity against a broader spectrum of resistant viral variants requires a comprehensive understanding of the molecular basis of drug resistance. In this study, 16 high-resolution crystal structures of four representative protease inhibitors - telaprevir, danoprevir, vaniprevir and MK-5172 - in complex with the wild-type protease and three major drug-resistant variants R155K, A156T and D168A, reveal unique molecular underpinnings of resistance to each drug. The drugs exhibit differential susceptibilities to these protease variants in both enzymatic and antiviral assays. Telaprevir, danoprevir and vaniprevir interact directly with sites that confer resistance upon mutation, while MK-5172 interacts in a unique conformation with the catalytic triad. This novel mode of MK-5172 binding explains its retained potency against two multi-drug-resistant variants, R155K and D168A. These findings define the molecular basis of HCV N3/4A protease inhibitor resistance and provide potential strategies for designing robust therapies against this rapidly evolving virus.	+
-		+
-	The Molecular Basis of Drug Resistance against Hepatitis C Virus NS3/4A Protease Inhibitors.,Romano KP, Ali A, Aydin C, Soumana D, Ozen A, Deveau LM, Silver C, Cao H, Newton A, Petropoulos CJ, Huang W, Schiffer CA PLoS Pathog. 2012 Jul;8(7):~~e1002832. Epub 2012 Jul 26. PMID:22910833<ref>PMID:22910833<~~/~~ref>~~	+
-		+
-	~~From MEDLINE®~~/~~PubMed®, a database of the U~~.S. ~~National Library of Medicine.<br>~~	+
-	</~~div>~~	+
-	~~<div class="pdbe-citations 3sv9" style="background-color:#fffaf0;"><~~/~~div>~~	+

	==See Also==		==See Also==
	*[[Virus protease 3D structures\|Virus protease 3D structures]]		*[[Virus protease 3D structures\|Virus protease 3D structures]]
-	== References ==
-	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: Hepatitis c virus ~~subtype~~ 1a]]	+	[[Category: Hepatitis C virus genotype 1a]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Romano~~, K P~~]]	+	[[Category: Romano KP]]
-	[[Category: Schiffer~~, C A]]~~	+	[[Category: Schiffer CA]]
-	~~[[Category: Drug design]]~~	+
-	~~[[Category: Drug resistance]]~~	+
-	~~[[Category: Hydrolase]]~~	+
-	~~[[Category: Hydrolase-inhibitor complex]]~~	+
-	~~[[Category: Protease inhibitor]]~~	+
-	~~[[Category: Serine protease]]~~	+
-	~~[[Category: Viral protein~~]]	+

OCA at 08:12, 29 June 2022

2022-06-29T08:12:01Z

←Older revision		Revision as of 08:12, 29 June 2022
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	==Crystal structure of NS3/4A protease variant A156T in complex with Telaprevir==		==Crystal structure of NS3/4A protease variant A156T in complex with Telaprevir==
-	<StructureSection load='3sv9' size='340' side='right' caption='[[3sv9]], [[Resolution\|resolution]] 1.60Å' scene=''>	+	<StructureSection load='3sv9' size='340' side='right'caption='[[3sv9]], [[Resolution\|resolution]] 1.60Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[3sv9]] is a 1 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/Hepatitis_c_virus_subtype_1a Hepatitis c virus subtype 1a]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3SV9 OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=3SV9 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[3sv9]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Hepatitis_c_virus_subtype_1a Hepatitis c virus subtype 1a]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3SV9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3SV9 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=SV6:(1S,3aR,6aS)-2-[(2S)-2-({(2S)-2-cyclohexyl-2-[(pyrazin-2-ylcarbonyl)amino]acetyl}amino)-3,3-dimethylbutanoyl]-N-[(2R,3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-yl]octahydrocyclopenta[c]pyrrole-1-carboxamide'>SV6</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=SV6:(1S,3aR,6aS)-2-[(2S)-2-({(2S)-2-cyclohexyl-2-[(pyrazin-2-ylcarbonyl)amino]acetyl}amino)-3,3-dimethylbutanoyl]-N-[(2R,3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-yl]octahydrocyclopenta[c]pyrrole-1-carboxamide'>SV6</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
-	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3su3\|3su3]], [[3su4\|3su4]], [[3su5\|3su5]], [[3su6\|3su6]], [[3sud\|3sud]], [[3sue\|3sue]], [[3suf\|3suf]], [[3sug\|3sug]], [[3sv6\|3sv6]], [[3sv7\|3sv7]], [[3sv8\|3sv8]]</td></tr>	+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3su3\|3su3]], [[3su4\|3su4]], [[3su5\|3su5]], [[3su6\|3su6]], [[3sud\|3sud]], [[3sue\|3sue]], [[3suf\|3suf]], [[3sug\|3sug]], [[3sv6\|3sv6]], [[3sv7\|3sv7]], [[3sv8\|3sv8]]</div></td></tr>
-	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">NS3-NS4A ([~~http~~://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=31646 Hepatitis C virus subtype 1a])</td></tr>	+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">NS3-NS4A ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=31646 Hepatitis C virus subtype 1a])</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=3sv9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3sv9 OCA], [~~http~~://pdbe.org/3sv9 PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=3sv9 RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/3sv9 PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=3sv9 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=3sv9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3sv9 OCA], [https://pdbe.org/3sv9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3sv9 RCSB], [https://www.ebi.ac.uk/pdbsum/3sv9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3sv9 ProSAT]</span></td></tr>
	</table>		</table>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
Line 18:		Line 18:
	</div>		</div>
	<div class="pdbe-citations 3sv9" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 3sv9" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Virus protease 3D structures\|Virus protease 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
Line 23:		Line 26:
	</StructureSection>		</StructureSection>
	[[Category: Hepatitis c virus subtype 1a]]		[[Category: Hepatitis c virus subtype 1a]]
		+	[[Category: Large Structures]]
	[[Category: Romano, K P]]		[[Category: Romano, K P]]
	[[Category: Schiffer, C A]]		[[Category: Schiffer, C A]]

OCA at 09:44, 8 November 2017

2017-11-08T09:44:00Z

←Older revision		Revision as of 09:44, 8 November 2017
Line 4:		Line 4:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[3sv9]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Hepatitis_c_virus_subtype_1a Hepatitis c virus subtype 1a]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3SV9 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3SV9 FirstGlance]. <br>		<table><tr><td colspan='2'>[[3sv9]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Hepatitis_c_virus_subtype_1a Hepatitis c virus subtype 1a]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3SV9 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3SV9 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=SV6:(1S,~~3AR~~,~~6AS~~)-2-[(2S)-2-({(2S)-2-~~CYCLOHEXYL~~-2-[(~~PYRAZIN~~-2-~~YLCARBONYL~~)~~AMINO~~]~~ACETYL~~}~~AMINO~~)-3,3-~~DIMETHYLBUTANOYL~~]-N-[(2R,3S)-1-(~~CYCLOPROPYLAMINO~~)-2-~~HYDROXY~~-1-~~OXOHEXAN~~-3-YL]~~OCTAHYDROCYCLOPENTA~~[C]~~PYRROLE~~-1-~~CARBOXAMIDE~~'>SV6</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=SV6:(1S,3aR,6aS)-2-[(2S)-2-({(2S)-2-cyclohexyl-2-[(pyrazin-2-ylcarbonyl)amino]acetyl}amino)-3,3-dimethylbutanoyl]-N-[(2R,3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-yl]octahydrocyclopenta[c]pyrrole-1-carboxamide'>SV6</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3su3\|3su3]], [[3su4\|3su4]], [[3su5\|3su5]], [[3su6\|3su6]], [[3sud\|3sud]], [[3sue\|3sue]], [[3suf\|3suf]], [[3sug\|3sug]], [[3sv6\|3sv6]], [[3sv7\|3sv7]], [[3sv8\|3sv8]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3su3\|3su3]], [[3su4\|3su4]], [[3su5\|3su5]], [[3su6\|3su6]], [[3sud\|3sud]], [[3sue\|3sue]], [[3suf\|3suf]], [[3sug\|3sug]], [[3sv6\|3sv6]], [[3sv7\|3sv7]], [[3sv8\|3sv8]]</td></tr>
	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">NS3-NS4A ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=31646 Hepatitis C virus subtype 1a])</td></tr>		<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">NS3-NS4A ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=31646 Hepatitis C virus subtype 1a])</td></tr>

OCA at 07:44, 11 August 2016

2016-08-11T07:44:57Z

←Older revision		Revision as of 07:44, 11 August 2016
Line 1:		Line 1:
		+
	==Crystal structure of NS3/4A protease variant A156T in complex with Telaprevir==		==Crystal structure of NS3/4A protease variant A156T in complex with Telaprevir==
	<StructureSection load='3sv9' size='340' side='right' caption='[[3sv9]], [[Resolution\|resolution]] 1.60Å' scene=''>		<StructureSection load='3sv9' size='340' side='right' caption='[[3sv9]], [[Resolution\|resolution]] 1.60Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[3sv9]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/~~Hepatitis_c_virus~~ Hepatitis c virus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3SV9 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3SV9 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[3sv9]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Hepatitis_c_virus_subtype_1a Hepatitis c virus subtype 1a]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3SV9 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3SV9 FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=SV6:(1S,3AR,6AS)-2-[(2S)-2-({(2S)-2-CYCLOHEXYL-2-[(PYRAZIN-2-YLCARBONYL)AMINO]ACETYL}AMINO)-3,3-DIMETHYLBUTANOYL]-N-[(2R,3S)-1-(CYCLOPROPYLAMINO)-2-HYDROXY-1-OXOHEXAN-3-YL]OCTAHYDROCYCLOPENTA[C]PYRROLE-1-CARBOXAMIDE'>SV6</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=SV6:(1S,3AR,6AS)-2-[(2S)-2-({(2S)-2-CYCLOHEXYL-2-[(PYRAZIN-2-YLCARBONYL)AMINO]ACETYL}AMINO)-3,3-DIMETHYLBUTANOYL]-N-[(2R,3S)-1-(CYCLOPROPYLAMINO)-2-HYDROXY-1-OXOHEXAN-3-YL]OCTAHYDROCYCLOPENTA[C]PYRROLE-1-CARBOXAMIDE'>SV6</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3su3\|3su3]], [[3su4\|3su4]], [[3su5\|3su5]], [[3su6\|3su6]], [[3sud\|3sud]], [[3sue\|3sue]], [[3suf\|3suf]], [[3sug\|3sug]], [[3sv6\|3sv6]], [[3sv7\|3sv7]], [[3sv8\|3sv8]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3su3\|3su3]], [[3su4\|3su4]], [[3su5\|3su5]], [[3su6\|3su6]], [[3sud\|3sud]], [[3sue\|3sue]], [[3suf\|3suf]], [[3sug\|3sug]], [[3sv6\|3sv6]], [[3sv7\|3sv7]], [[3sv8\|3sv8]]</td></tr>
-	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">NS3-NS4A ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=~~11103~~ Hepatitis C virus])</td></tr>	+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">NS3-NS4A ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=31646 Hepatitis C virus subtype 1a])</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=3sv9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3sv9 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3sv9 RCSB], [http://www.ebi.ac.uk/pdbsum/3sv9 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=3sv9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3sv9 OCA], [http://pdbe.org/3sv9 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3sv9 RCSB], [http://www.ebi.ac.uk/pdbsum/3sv9 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3sv9 ProSAT]</span></td></tr>
	</table>		</table>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
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	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 3sv9" style="background-color:#fffaf0;"></div>
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: Hepatitis c virus]]	+	[[Category: Hepatitis c virus subtype 1a]]
	[[Category: Romano, K P]]		[[Category: Romano, K P]]
	[[Category: Schiffer, C A]]		[[Category: Schiffer, C A]]

OCA at 09:47, 4 January 2015

2015-01-04T09:47:26Z

←Older revision		Revision as of 09:47, 4 January 2015
Line 3:		Line 3:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[3sv9]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Hepatitis_c_virus Hepatitis c virus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3SV9 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3SV9 FirstGlance]. <br>		<table><tr><td colspan='2'>[[3sv9]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Hepatitis_c_virus Hepatitis c virus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3SV9 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3SV9 FirstGlance]. <br>
-	</td></tr><tr><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=SV6:(1S,3AR,6AS)-2-[(2S)-2-({(2S)-2-CYCLOHEXYL-2-[(PYRAZIN-2-YLCARBONYL)AMINO]ACETYL}AMINO)-3,3-DIMETHYLBUTANOYL]-N-[(2R,3S)-1-(CYCLOPROPYLAMINO)-2-HYDROXY-1-OXOHEXAN-3-YL]OCTAHYDROCYCLOPENTA[C]PYRROLE-1-CARBOXAMIDE'>SV6</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene><br>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=SV6:(1S,3AR,6AS)-2-[(2S)-2-({(2S)-2-CYCLOHEXYL-2-[(PYRAZIN-2-YLCARBONYL)AMINO]ACETYL}AMINO)-3,3-DIMETHYLBUTANOYL]-N-[(2R,3S)-1-(CYCLOPROPYLAMINO)-2-HYDROXY-1-OXOHEXAN-3-YL]OCTAHYDROCYCLOPENTA[C]PYRROLE-1-CARBOXAMIDE'>SV6</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
-	<tr><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3su3\|3su3]], [[3su4\|3su4]], [[3su5\|3su5]], [[3su6\|3su6]], [[3sud\|3sud]], [[3sue\|3sue]], [[3suf\|3suf]], [[3sug\|3sug]], [[3sv6\|3sv6]], [[3sv7\|3sv7]], [[3sv8\|3sv8]]</td></tr>	+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3su3\|3su3]], [[3su4\|3su4]], [[3su5\|3su5]], [[3su6\|3su6]], [[3sud\|3sud]], [[3sue\|3sue]], [[3suf\|3suf]], [[3sug\|3sug]], [[3sv6\|3sv6]], [[3sv7\|3sv7]], [[3sv8\|3sv8]]</td></tr>
-	<tr><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">NS3-NS4A ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=11103 Hepatitis C virus])</td></tr>	+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">NS3-NS4A ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=11103 Hepatitis C virus])</td></tr>
-	<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3sv9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3sv9 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3sv9 RCSB], [http://www.ebi.ac.uk/pdbsum/3sv9 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=3sv9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3sv9 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3sv9 RCSB], [http://www.ebi.ac.uk/pdbsum/3sv9 PDBsum]</span></td></tr>
-	<table>	+	</table>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 21:		Line 21:
	</StructureSection>		</StructureSection>
	[[Category: Hepatitis c virus]]		[[Category: Hepatitis c virus]]
-	[[Category: Romano, K P.]]	+	[[Category: Romano, K P]]
-	[[Category: Schiffer, C A.]]	+	[[Category: Schiffer, C A]]
	[[Category: Drug design]]		[[Category: Drug design]]
	[[Category: Drug resistance]]		[[Category: Drug resistance]]

OCA at 07:02, 9 June 2014

2014-06-09T07:02:36Z

←Older revision		Revision as of 07:02, 9 June 2014
Line 1:		Line 1:
-	[[~~Image:~~3sv9.~~jpg~~\|~~left~~\|~~200px~~]]	+	==Crystal structure of NS3/4A protease variant A156T in complex with Telaprevir==
		+	<StructureSection load='3sv9' size='340' side='right' caption='[[3sv9]], [[Resolution\|resolution]] 1.60Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[3sv9]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Hepatitis_c_virus Hepatitis c virus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3SV9 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3SV9 FirstGlance]. <br>
		+	</td></tr><tr><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=SV6:(1S,3AR,6AS)-2-[(2S)-2-({(2S)-2-CYCLOHEXYL-2-[(PYRAZIN-2-YLCARBONYL)AMINO]ACETYL}AMINO)-3,3-DIMETHYLBUTANOYL]-N-[(2R,3S)-1-(CYCLOPROPYLAMINO)-2-HYDROXY-1-OXOHEXAN-3-YL]OCTAHYDROCYCLOPENTA[C]PYRROLE-1-CARBOXAMIDE'>SV6</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene><br>
		+	<tr><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3su3\|3su3]], [[3su4\|3su4]], [[3su5\|3su5]], [[3su6\|3su6]], [[3sud\|3sud]], [[3sue\|3sue]], [[3suf\|3suf]], [[3sug\|3sug]], [[3sv6\|3sv6]], [[3sv7\|3sv7]], [[3sv8\|3sv8]]</td></tr>
		+	<tr><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">NS3-NS4A ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=11103 Hepatitis C virus])</td></tr>
		+	<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3sv9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3sv9 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3sv9 RCSB], [http://www.ebi.ac.uk/pdbsum/3sv9 PDBsum]</span></td></tr>
		+	<table>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Hepatitis C virus (HCV) infects over 170 million people worldwide and is the leading cause of chronic liver diseases, including cirrhosis, liver failure, and liver cancer. Available antiviral therapies cause severe side effects and are effective only for a subset of patients, though treatment outcomes have recently been improved by the combination therapy now including boceprevir and telaprevir, which inhibit the viral NS3/4A protease. Despite extensive efforts to develop more potent next-generation protease inhibitors, however, the long-term efficacy of this drug class is challenged by the rapid emergence of resistance. Single-site mutations at protease residues R155, A156 and D168 confer resistance to nearly all inhibitors in clinical development. Thus, developing the next-generation of drugs that retain activity against a broader spectrum of resistant viral variants requires a comprehensive understanding of the molecular basis of drug resistance. In this study, 16 high-resolution crystal structures of four representative protease inhibitors - telaprevir, danoprevir, vaniprevir and MK-5172 - in complex with the wild-type protease and three major drug-resistant variants R155K, A156T and D168A, reveal unique molecular underpinnings of resistance to each drug. The drugs exhibit differential susceptibilities to these protease variants in both enzymatic and antiviral assays. Telaprevir, danoprevir and vaniprevir interact directly with sites that confer resistance upon mutation, while MK-5172 interacts in a unique conformation with the catalytic triad. This novel mode of MK-5172 binding explains its retained potency against two multi-drug-resistant variants, R155K and D168A. These findings define the molecular basis of HCV N3/4A protease inhibitor resistance and provide potential strategies for designing robust therapies against this rapidly evolving virus.

-	~~{{STRUCTURE_3sv9\| PDB=3sv9 \| SCENE= }}~~	+	The Molecular Basis of Drug Resistance against Hepatitis C Virus NS3/4A Protease Inhibitors.,Romano KP, Ali A, Aydin C, Soumana D, Ozen A, Deveau LM, Silver C, Cao H, Newton A, Petropoulos CJ, Huang W, Schiffer CA PLoS Pathog. 2012 Jul;8(7):e1002832. Epub 2012 Jul 26. PMID:22910833<ref>PMID:22910833</ref>

-	~~===Crystal structure~~ of ~~NS3~~/~~4A protease variant A156T in complex with Telaprevir===~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-		+	</div>
-	~~{{ABSTRACT_PUBMED_22910833}}~~	+	== References ==
-		+	<references/>
-	==~~About this Structure~~==	+	__TOC__
-	~~[[3sv9]] is a 1 chain structure with sequence from [http:~~//~~en.wikipedia.org/wiki/Hepatitis_c_virus Hepatitis c virus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3SV9 OCA].~~	+	</StructureSection>
	[[Category: Hepatitis c virus]]		[[Category: Hepatitis c virus]]
	[[Category: Romano, K P.]]		[[Category: Romano, K P.]]

OCA at 05:18, 5 September 2012

2012-09-05T05:18:14Z

←Older revision		Revision as of 05:18, 5 September 2012
Line 1:		Line 1:
-	~~'''Unreleased structure'''~~	+	[[Image:3sv9.jpg\|left\|200px]]

-	~~The entry~~ 3sv9 ~~is ON HOLD~~ ~~until Oct 05 2013~~	+	{{STRUCTURE_3sv9\| PDB=3sv9 \| SCENE= }}

-	~~Authors: Schiffer, C.A., Romano, K.P.~~	+	===Crystal structure of NS3/4A protease variant A156T in complex with Telaprevir===

-	~~Description: Crystal~~ structure ~~of NS3~~/~~4A protease variant A156T in~~ complex ~~with Telaprevir~~	+	{{ABSTRACT_PUBMED_22910833}}
		+
		+	==About this Structure==
		+	[[3sv9]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Hepatitis_c_virus Hepatitis c virus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3SV9 OCA].
		+	[[Category: Hepatitis c virus]]
		+	[[Category: Romano, K P.]]
		+	[[Category: Schiffer, C A.]]
		+	[[Category: Drug design]]
		+	[[Category: Drug resistance]]
		+	[[Category: Hydrolase]]
		+	[[Category: Hydrolase-inhibitor complex]]
		+	[[Category: Protease inhibitor]]
		+	[[Category: Serine protease]]
		+	[[Category: Viral protein]]

OCA at 07:34, 11 July 2012

2012-07-11T07:34:32Z

←Older revision		Revision as of 07:34, 11 July 2012
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 3sv9 is ON HOLD until ~~Paper Publication~~	+	The entry 3sv9 is ON HOLD until Oct 05 2013

	Authors: Schiffer, C.A., Romano, K.P.		Authors: Schiffer, C.A., Romano, K.P.

	Description: Crystal structure of NS3/4A protease variant A156T in complex with Telaprevir		Description: Crystal structure of NS3/4A protease variant A156T in complex with Telaprevir

OCA at 05:50, 17 August 2011

2011-08-17T05:50:48Z

←Older revision		Revision as of 05:50, 17 August 2011
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 3sv9 is ON HOLD	+	The entry 3sv9 is ON HOLD until Paper Publication

	Authors: Schiffer, C.A., Romano, K.P.		Authors: Schiffer, C.A., Romano, K.P.

	Description: Crystal structure of NS3/4A protease variant A156T in complex with Telaprevir		Description: Crystal structure of NS3/4A protease variant A156T in complex with Telaprevir

OCA: Protected "3sv9" [edit=sysop:move=sysop]

2011-07-20T06:17:59Z

Protected "3sv9" [edit=sysop:move=sysop]

←Older revision

Revision as of 06:17, 20 July 2011