3sud - Revision history

OCA at 09:57, 1 March 2024

OCA — Fri, 01 Mar 2024 09:57:17 GMT

←Older revision		Revision as of 09:57, 1 March 2024
Line 3:		Line 3:
	<StructureSection load='3sud' size='340' side='right'caption='[[3sud]], [[Resolution\|resolution]] 1.96Å' scene=''>		<StructureSection load='3sud' size='340' side='right'caption='[[3sud]], [[Resolution\|resolution]] 1.96Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[3sud]] is a 4 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=3SUD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3SUD FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[3sud]] is a 4 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=3SUD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3SUD FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=SUE:(1AR,5S,8S,10R,22AR)-5-TERT-BUTYL-N-{(1R,2S)-1-[(CYCLOPROPYLSULFONYL)CARBAMOYL]-2-ETHENYLCYCLOPROPYL}-14-METHOXY-3,6-DIOXO-1,1A,3,4,5,6,9,10,18,19,20,21,22,22A-TETRADECAHYDRO-8H-7,10-METHANOCYCLOPROPA[18,19][1,10,3,6]DIOXADIAZACYCLONONADECINO[11,12-B]QUINOXALINE-8-CARBOXAMIDE'>SUE</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]] 1.96Å</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]], [[3sue\|3sue]], [[3suf\|3suf]], [[3sug\|3sug]], [[3sv6\|3sv6]], [[3sv7\|3sv7]], [[3sv8\|3sv8]], [[3sv9\|3sv9]]</div></td></tr>	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=SUE:(1AR,5S,8S,10R,22AR)-5-TERT-BUTYL-N-{(1R,2S)-1-[(CYCLOPROPYLSULFONYL)CARBAMOYL]-2-ETHENYLCYCLOPROPYL}-14-METHOXY-3,6-DIOXO-1,1A,3,4,5,6,9,10,18,19,20,21,22,22A-TETRADECAHYDRO-8H-7,10-METHANOCYCLOPROPA[18,19][1,10,3,6]DIOXADIAZACYCLONONADECINO[11,12-B]QUINOXALINE-8-CARBOXAMIDE'>SUE</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=3sud FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3sud OCA], [https://pdbe.org/3sud PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3sud RCSB], [https://www.ebi.ac.uk/pdbsum/3sud PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3sud 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=3sud FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3sud OCA], [https://pdbe.org/3sud PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3sud RCSB], [https://www.ebi.ac.uk/pdbsum/3sud PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3sud 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 3sud" 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: Hcv]]~~	+
-	~~[[Category: Hydrolase-inhibitor complex]]~~	+
-	~~[[Category: Protease inhibitor]]~~	+
-	~~[[Category: Serine protease]]~~	+
-	~~[[Category: Viral protein~~]]	+

OCA at 08:10, 29 June 2022

OCA — Wed, 29 Jun 2022 08:10:52 GMT

←Older revision		Revision as of 08:10, 29 June 2022
Line 3:		Line 3:
	<StructureSection load='3sud' size='340' side='right'caption='[[3sud]], [[Resolution\|resolution]] 1.96Å' scene=''>		<StructureSection load='3sud' size='340' side='right'caption='[[3sud]], [[Resolution\|resolution]] 1.96Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[3sud]] is a 4 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=3SUD OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=3SUD FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[3sud]] is a 4 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=3SUD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3SUD FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=SUE:(1AR,5S,8S,10R,22AR)-5-TERT-BUTYL-N-{(1R,2S)-1-[(CYCLOPROPYLSULFONYL)CARBAMOYL]-2-ETHENYLCYCLOPROPYL}-14-METHOXY-3,6-DIOXO-1,1A,3,4,5,6,9,10,18,19,20,21,22,22A-TETRADECAHYDRO-8H-7,10-METHANOCYCLOPROPA[18,19][1,10,3,6]DIOXADIAZACYCLONONADECINO[11,12-B]QUINOXALINE-8-CARBOXAMIDE'>SUE</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=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=SUE:(1AR,5S,8S,10R,22AR)-5-TERT-BUTYL-N-{(1R,2S)-1-[(CYCLOPROPYLSULFONYL)CARBAMOYL]-2-ETHENYLCYCLOPROPYL}-14-METHOXY-3,6-DIOXO-1,1A,3,4,5,6,9,10,18,19,20,21,22,22A-TETRADECAHYDRO-8H-7,10-METHANOCYCLOPROPA[18,19][1,10,3,6]DIOXADIAZACYCLONONADECINO[11,12-B]QUINOXALINE-8-CARBOXAMIDE'>SUE</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]], [[3sue\|3sue]], [[3suf\|3suf]], [[3sug\|3sug]], [[3sv6\|3sv6]], [[3sv7\|3sv7]], [[3sv8\|3sv8]], [[3sv9\|3sv9]]</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]], [[3sue\|3sue]], [[3suf\|3suf]], [[3sug\|3sug]], [[3sv6\|3sv6]], [[3sv7\|3sv7]], [[3sv8\|3sv8]], [[3sv9\|3sv9]]</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=3sud FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3sud OCA], [~~http~~://pdbe.org/3sud PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=3sud RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/3sud PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=3sud 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=3sud FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3sud OCA], [https://pdbe.org/3sud PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3sud RCSB], [https://www.ebi.ac.uk/pdbsum/3sud PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3sud 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 3sud" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 3sud" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Virus protease 3D structures\|Virus protease 3D structures]]
	== References ==		== References ==
	<references/>		<references/>

OCA at 15:33, 11 December 2019

OCA — Wed, 11 Dec 2019 15:33:56 GMT

←Older revision		Revision as of 15:33, 11 December 2019
Line 1:		Line 1:

	==Crystal structure of NS3/4A protease in complex with MK-5172==		==Crystal structure of NS3/4A protease in complex with MK-5172==
-	<StructureSection load='3sud' size='340' side='right' caption='[[3sud]], [[Resolution\|resolution]] 1.96Å' scene=''>	+	<StructureSection load='3sud' size='340' side='right'caption='[[3sud]], [[Resolution\|resolution]] 1.96Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[3sud]] is a 4 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=3SUD OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3SUD FirstGlance]. <br>		<table><tr><td colspan='2'>[[3sud]] is a 4 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=3SUD OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3SUD FirstGlance]. <br>
Line 23:		Line 23:
	</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 13:08, 11 August 2016

OCA — Thu, 11 Aug 2016 13:08:01 GMT

←Older revision		Revision as of 13:08, 11 August 2016
Line 1:		Line 1:
		+
	==Crystal structure of NS3/4A protease in complex with MK-5172==		==Crystal structure of NS3/4A protease in complex with MK-5172==
	<StructureSection load='3sud' size='340' side='right' caption='[[3sud]], [[Resolution\|resolution]] 1.96Å' scene=''>		<StructureSection load='3sud' size='340' side='right' caption='[[3sud]], [[Resolution\|resolution]] 1.96Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[3sud]] is a 4 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=3SUD OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3SUD FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[3sud]] is a 4 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=3SUD OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3SUD FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=SUE:(1AR,5S,8S,10R,22AR)-5-TERT-BUTYL-N-{(1R,2S)-1-[(CYCLOPROPYLSULFONYL)CARBAMOYL]-2-ETHENYLCYCLOPROPYL}-14-METHOXY-3,6-DIOXO-1,1A,3,4,5,6,9,10,18,19,20,21,22,22A-TETRADECAHYDRO-8H-7,10-METHANOCYCLOPROPA[18,19][1,10,3,6]DIOXADIAZACYCLONONADECINO[11,12-B]QUINOXALINE-8-CARBOXAMIDE'>SUE</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=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=SUE:(1AR,5S,8S,10R,22AR)-5-TERT-BUTYL-N-{(1R,2S)-1-[(CYCLOPROPYLSULFONYL)CARBAMOYL]-2-ETHENYLCYCLOPROPYL}-14-METHOXY-3,6-DIOXO-1,1A,3,4,5,6,9,10,18,19,20,21,22,22A-TETRADECAHYDRO-8H-7,10-METHANOCYCLOPROPA[18,19][1,10,3,6]DIOXADIAZACYCLONONADECINO[11,12-B]QUINOXALINE-8-CARBOXAMIDE'>SUE</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]], [[3sue\|3sue]], [[3suf\|3suf]], [[3sug\|3sug]], [[3sv6\|3sv6]], [[3sv7\|3sv7]], [[3sv8\|3sv8]], [[3sv9\|3sv9]]</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]], [[3sue\|3sue]], [[3suf\|3suf]], [[3sug\|3sug]], [[3sv6\|3sv6]], [[3sv7\|3sv7]], [[3sv8\|3sv8]], [[3sv9\|3sv9]]</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=3sud FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3sud OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3sud RCSB], [http://www.ebi.ac.uk/pdbsum/3sud 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=3sud FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3sud OCA], [http://pdbe.org/3sud PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3sud RCSB], [http://www.ebi.ac.uk/pdbsum/3sud PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3sud ProSAT]</span></td></tr>
	</table>		</table>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
Line 16:		Line 17:
	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 3sud" 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 10:05, 4 January 2015

OCA — Sun, 04 Jan 2015 10:05:27 GMT

←Older revision		Revision as of 10:05, 4 January 2015
Line 3:		Line 3:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[3sud]] is a 4 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=3SUD OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3SUD FirstGlance]. <br>		<table><tr><td colspan='2'>[[3sud]] is a 4 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=3SUD OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3SUD FirstGlance]. <br>
-	</td></tr><tr><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=SUE:(1AR,5S,8S,10R,22AR)-5-TERT-BUTYL-N-{(1R,2S)-1-[(CYCLOPROPYLSULFONYL)CARBAMOYL]-2-ETHENYLCYCLOPROPYL}-14-METHOXY-3,6-DIOXO-1,1A,3,4,5,6,9,10,18,19,20,21,22,22A-TETRADECAHYDRO-8H-7,10-METHANOCYCLOPROPA[18,19][1,10,3,6]DIOXADIAZACYCLONONADECINO[11,12-B]QUINOXALINE-8-CARBOXAMIDE'>SUE</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=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=SUE:(1AR,5S,8S,10R,22AR)-5-TERT-BUTYL-N-{(1R,2S)-1-[(CYCLOPROPYLSULFONYL)CARBAMOYL]-2-ETHENYLCYCLOPROPYL}-14-METHOXY-3,6-DIOXO-1,1A,3,4,5,6,9,10,18,19,20,21,22,22A-TETRADECAHYDRO-8H-7,10-METHANOCYCLOPROPA[18,19][1,10,3,6]DIOXADIAZACYCLONONADECINO[11,12-B]QUINOXALINE-8-CARBOXAMIDE'>SUE</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]], [[3sue\|3sue]], [[3suf\|3suf]], [[3sug\|3sug]], [[3sv6\|3sv6]], [[3sv7\|3sv7]], [[3sv8\|3sv8]], [[3sv9\|3sv9]]</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]], [[3sue\|3sue]], [[3suf\|3suf]], [[3sug\|3sug]], [[3sv6\|3sv6]], [[3sv7\|3sv7]], [[3sv8\|3sv8]], [[3sv9\|3sv9]]</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=3sud FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3sud OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3sud RCSB], [http://www.ebi.ac.uk/pdbsum/3sud 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=3sud FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3sud OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3sud RCSB], [http://www.ebi.ac.uk/pdbsum/3sud 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 06:51, 25 June 2014

OCA — Wed, 25 Jun 2014 06:51:49 GMT

←Older revision		Revision as of 06:51, 25 June 2014
Line 1:		Line 1:
-	[[~~Image:~~3sud.~~jpg~~\|~~left~~\|~~200px~~]]	+	==Crystal structure of NS3/4A protease in complex with MK-5172==
		+	<StructureSection load='3sud' size='340' side='right' caption='[[3sud]], [[Resolution\|resolution]] 1.96Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[3sud]] is a 4 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=3SUD OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3SUD FirstGlance]. <br>
		+	</td></tr><tr><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=SUE:(1AR,5S,8S,10R,22AR)-5-TERT-BUTYL-N-{(1R,2S)-1-[(CYCLOPROPYLSULFONYL)CARBAMOYL]-2-ETHENYLCYCLOPROPYL}-14-METHOXY-3,6-DIOXO-1,1A,3,4,5,6,9,10,18,19,20,21,22,22A-TETRADECAHYDRO-8H-7,10-METHANOCYCLOPROPA[18,19][1,10,3,6]DIOXADIAZACYCLONONADECINO[11,12-B]QUINOXALINE-8-CARBOXAMIDE'>SUE</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]], [[3sue\|3sue]], [[3suf\|3suf]], [[3sug\|3sug]], [[3sv6\|3sv6]], [[3sv7\|3sv7]], [[3sv8\|3sv8]], [[3sv9\|3sv9]]</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=3sud FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3sud OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3sud RCSB], [http://www.ebi.ac.uk/pdbsum/3sud 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_3sud\| PDB=3sud \| 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 in complex with MK-5172===~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-		+	</div>
-	~~{{ABSTRACT_PUBMED_22910833}}~~	+	== References ==
-		+	<references/>
-	==~~About this Structure~~==	+	__TOC__
-	~~[[3sud]] is a 4 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=3SUD OCA].~~	+	</StructureSection>
	[[Category: Hepatitis c virus]]		[[Category: Hepatitis c virus]]
	[[Category: Romano, K P.]]		[[Category: Romano, K P.]]

OCA at 07:14, 19 September 2012

OCA — Wed, 19 Sep 2012 07:14:50 GMT

←Older revision		Revision as of 07:14, 19 September 2012
Line 1:		Line 1:
-	~~'''Unreleased structure'''~~	+	[[Image:3sud.jpg\|left\|200px]]

-	~~The entry~~ 3sud ~~is ON HOLD~~ ~~until Paper Publication~~	+	{{STRUCTURE_3sud\| PDB=3sud \| SCENE= }}

-	~~Authors: Schiffer, C.A., Romano, K.P.~~	+	===Crystal structure of NS3/4A protease in complex with MK-5172===

-	~~Description: Crystal~~ structure ~~of NS3/4A protease in complex~~ with MK-~~5172~~	+	{{ABSTRACT_PUBMED_22910833}}
		+
		+	==About this Structure==
		+	[[3sud]] is a 4 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=3SUD OCA].
		+	[[Category: Hepatitis c virus]]
		+	[[Category: Romano, K P.]]
		+	[[Category: Schiffer, C A.]]
		+	[[Category: Drug design]]
		+	[[Category: Drug resistance]]
		+	[[Category: Hcv]]
		+	[[Category: Hydrolase-inhibitor complex]]
		+	[[Category: Protease inhibitor]]
		+	[[Category: Serine protease]]
		+	[[Category: Viral protein]]

OCA at 04:36, 12 September 2012

OCA — Wed, 12 Sep 2012 04:36:59 GMT

←Older revision		Revision as of 04:36, 12 September 2012
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 3sud is ON HOLD until ~~sometime in the future~~	+	The entry 3sud 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 in complex with MK-5172		Description: Crystal structure of NS3/4A protease in complex with MK-5172

OCA at 04:37, 5 September 2012

OCA — Wed, 05 Sep 2012 04:37:59 GMT

←Older revision		Revision as of 04:37, 5 September 2012
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 3sud is ON HOLD	+	The entry 3sud is ON HOLD until sometime in the future

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

	Description: Crystal structure of NS3/4A protease in complex with MK-5172		Description: Crystal structure of NS3/4A protease in complex with MK-5172

OCA at 05:11, 1 August 2012

OCA — Wed, 01 Aug 2012 05:11:38 GMT

←Older revision		Revision as of 05:11, 1 August 2012
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 3sud is ON HOLD ~~until sometime in the future~~	+	The entry 3sud is ON HOLD

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

	Description: Crystal structure of NS3/4A protease in complex with MK-5172		Description: Crystal structure of NS3/4A protease in complex with MK-5172