3suf - Revision history

OCA at 09:57, 1 March 2024

2024-03-01T09:57:17Z

← Older revision		Revision as of 09:57, 1 March 2024
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	<StructureSection load='3suf' size='340' side='right'caption='[[3suf]], [[Resolution\|resolution]] 2.19Å' scene=''>		<StructureSection load='3suf' size='340' side='right'caption='[[3suf]], [[Resolution\|resolution]] 2.19Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[3suf]] 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=3SUF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3SUF FirstGlance]. <br>		<table><tr><td colspan='2'>[[3suf]] 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=3SUF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3SUF 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]] 2.19Å</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]], [[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=3suf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3suf OCA], [https://pdbe.org/3suf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3suf RCSB], [https://www.ebi.ac.uk/pdbsum/3suf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3suf 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=3suf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3suf OCA], [https://pdbe.org/3suf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3suf RCSB], [https://www.ebi.ac.uk/pdbsum/3suf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3suf 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 3suf" 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

2022-06-29T08:10:58Z

← Older revision		Revision as of 08:10, 29 June 2022
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	<StructureSection load='3suf' size='340' side='right'caption='[[3suf]], [[Resolution\|resolution]] 2.19Å' scene=''>		<StructureSection load='3suf' size='340' side='right'caption='[[3suf]], [[Resolution\|resolution]] 2.19Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[3suf]] 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=3SUF OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=3SUF FirstGlance]. <br>		<table><tr><td colspan='2'>[[3suf]] 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=3SUF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3SUF 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]], [[3sud\|3sud]], [[3sue\|3sue]], [[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]], [[3sud\|3sud]], [[3sue\|3sue]], [[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=3suf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3suf OCA], [~~http~~://pdbe.org/3suf PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=3suf RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/3suf PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=3suf 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=3suf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3suf OCA], [https://pdbe.org/3suf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3suf RCSB], [https://www.ebi.ac.uk/pdbsum/3suf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3suf ProSAT]</span></td></tr>
	</table>		</table>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
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	</div>		</div>
	<div class="pdbe-citations 3suf" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 3suf" style="background-color:#fffaf0;"></div>

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

OCA at 15:34, 11 December 2019

2019-12-11T15:34:08Z

← Older revision		Revision as of 15:34, 11 December 2019
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	==Crystal structure of NS3/4A protease variant D168A in complex with MK-5172==		==Crystal structure of NS3/4A protease variant D168A in complex with MK-5172==
	<StructureSection load='3suf' size='340' side='right' caption='[[3suf]], [[Resolution\|resolution]] 2.19Å' scene=''>		<StructureSection load='3suf' size='340' side='right'caption='[[3suf]], [[Resolution\|resolution]] 2.19Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[3suf]] 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=3SUF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3SUF FirstGlance]. <br>		<table><tr><td colspan='2'>[[3suf]] 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=3SUF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3SUF FirstGlance]. <br>
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	</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 16:50, 11 August 2016

2016-08-11T16:50:07Z

← Older revision		Revision as of 16:50, 11 August 2016
Line 1:		Line 1:

	==Crystal structure of NS3/4A protease variant D168A in complex with MK-5172==		==Crystal structure of NS3/4A protease variant D168A in complex with MK-5172==
	<StructureSection load='3suf' size='340' side='right' caption='[[3suf]], [[Resolution\|resolution]] 2.19Å' scene=''>		<StructureSection load='3suf' size='340' side='right' caption='[[3suf]], [[Resolution\|resolution]] 2.19Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[3suf]] 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=3SUF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3SUF FirstGlance]. <br>		<table><tr><td colspan='2'>[[3suf]] 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=3SUF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3SUF 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]], [[3sud\|3sud]], [[3sue\|3sue]], [[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]], [[3sud\|3sud]], [[3sue\|3sue]], [[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=3suf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3suf OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3suf RCSB], [http://www.ebi.ac.uk/pdbsum/3suf 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=3suf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3suf OCA], [http://pdbe.org/3suf PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3suf RCSB], [http://www.ebi.ac.uk/pdbsum/3suf PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3suf 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 3suf" 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 10:16, 4 January 2015

2015-01-04T10:16:06Z

← Older revision		Revision as of 10:16, 4 January 2015
Line 3:		Line 3:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[3suf]] 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=3SUF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3SUF FirstGlance]. <br>		<table><tr><td colspan='2'>[[3suf]] 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=3SUF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3SUF 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]], [[3sud\|3sud]], [[3sue\|3sue]], [[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]], [[3sud\|3sud]], [[3sue\|3sue]], [[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=3suf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3suf OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3suf RCSB], [http://www.ebi.ac.uk/pdbsum/3suf 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=3suf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3suf OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3suf RCSB], [http://www.ebi.ac.uk/pdbsum/3suf 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 06:50, 25 June 2014

2014-06-25T06:50:16Z

← Older revision		Revision as of 06:50, 25 June 2014
Line 1:		Line 1:
	[[~~Image~~:~~3suf~~.~~jpg~~\|~~left~~\|~~200px~~]]		==Crystal structure of NS3/4A protease variant D168A in complex with MK-5172==
			<StructureSection load='3suf' size='340' side='right' caption='[[3suf]], [[Resolution\|resolution]] 2.19Å' scene=''>
			== Structural highlights ==
			<table><tr><td colspan='2'>[[3suf]] 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=3SUF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3SUF 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]], [[3sud\|3sud]], [[3sue\|3sue]], [[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=3suf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3suf OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3suf RCSB], [http://www.ebi.ac.uk/pdbsum/3suf 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_3suf\| PDB=3suf \| 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 D168A 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__
	~~[[3suf]] 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=3SUF OCA].~~		</StructureSection>
	[[Category: Hepatitis c virus]]		[[Category: Hepatitis c virus]]
	[[Category: Romano, K P.]]		[[Category: Romano, K P.]]

OCA at 07:13, 19 September 2012

2012-09-19T07:13:47Z

← Older revision		Revision as of 07:13, 19 September 2012
Line 1:		Line 1:
	~~'''Unreleased structure'''~~		[[Image:3suf.jpg\|left\|200px]]

	~~The entry~~ 3suf ~~is ON HOLD~~ ~~until Paper Publication~~		{{STRUCTURE_3suf\| PDB=3suf \| SCENE= }}

	~~Authors: Schiffer, C.A., Romano, K.P.~~		===Crystal structure of NS3/4A protease variant D168A in complex with MK-5172===

	~~Description~~: ~~Crystal structure of NS3~~/4A protease ~~variant D168A in complex with MK-5172~~		{{ABSTRACT_PUBMED_22910833}}

			==About this Structure==
			[[3suf]] 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=3SUF 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 04:37, 12 September 2012

2012-09-12T04:37:03Z

← Older revision		Revision as of 04:37, 12 September 2012
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

	The entry 3suf is ON HOLD until ~~sometime in the future~~		The entry 3suf 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 D168A in complex with MK-5172		Description: Crystal structure of NS3/4A protease variant D168A in complex with MK-5172

OCA at 04:38, 5 September 2012

2012-09-05T04:38:03Z

← Older revision		Revision as of 04:38, 5 September 2012
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

	The entry 3suf is ON HOLD		The entry 3suf 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 variant D168A in complex with MK-5172		Description: Crystal structure of NS3/4A protease variant D168A in complex with MK-5172

OCA at 05:11, 1 August 2012

2012-08-01T05:11:42Z

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

	The entry 3suf is ON HOLD ~~until sometime in the future~~		The entry 3suf is ON HOLD

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

	Description: Crystal structure of NS3/4A protease variant D168A in complex with MK-5172		Description: Crystal structure of NS3/4A protease variant D168A in complex with MK-5172