6nzv - Revision history

OCA at 07:02, 11 October 2023

2023-10-11T07:02:17Z

←Older revision		Revision as of 07:02, 11 October 2023
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	<StructureSection load='6nzv' size='340' side='right'caption='[[6nzv]], [[Resolution\|resolution]] 1.55Å' scene=''>		<StructureSection load='6nzv' size='340' side='right'caption='[[6nzv]], [[Resolution\|resolution]] 1.55Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6nzv]] 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=6NZV OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=6NZV FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6nzv]] 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=6NZV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6NZV FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=L9J:(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-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'>L9J</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 1.55Å</td></tr>
-	~~<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[6nzt\|6nzt]]~~</td></tr>	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=L9J:(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-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'>L9J</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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=6nzv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6nzv OCA], [~~http~~://pdbe.org/6nzv PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=6nzv RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/6nzv PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=6nzv 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=6nzv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6nzv OCA], [https://pdbe.org/6nzv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6nzv RCSB], [https://www.ebi.ac.uk/pdbsum/6nzv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6nzv ProSAT]</span></td></tr>
	</table>		</table>
		+	== Function ==
		+	[https://www.uniprot.org/uniprot/S4UY05_9HEPC S4UY05_9HEPC]
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 17:		Line 19:
	</div>		</div>
	<div class="pdbe-citations 6nzv" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 6nzv" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Virus protease 3D structures\|Virus protease 3D structures]]
	== References ==		== References ==
	<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: Appleby~~, T C~~]]	+	[[Category: Appleby TC]]
-	[[Category: Taylor~~, J G]]~~	+	[[Category: Taylor JG]]
-	~~[[Category: Hepatitis c virus]]~~	+
-	~~[[Category: Viral protease inhibitor]]~~	+
-	~~[[Category: Viral protein]]~~	+
-	~~[[Category: Viral protein-inhibitor complex]]~~	+
-	~~[[Category: Voxilaprevir~~]]	+

OCA at 06:38, 21 August 2019

2019-08-21T06:38:45Z

←Older revision		Revision as of 06:38, 21 August 2019
Line 3:		Line 3:
	<StructureSection load='6nzv' size='340' side='right'caption='[[6nzv]], [[Resolution\|resolution]] 1.55Å' scene=''>		<StructureSection load='6nzv' size='340' side='right'caption='[[6nzv]], [[Resolution\|resolution]] 1.55Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6nzv]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6NZV OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6NZV FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6nzv]] 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=6NZV OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6NZV FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=L9J:(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-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'>L9J</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=L9J:(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-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'>L9J</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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">[[6nzt\|6nzt]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[6nzt\|6nzt]]</td></tr>
Line 21:		Line 21:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Hepatitis c virus subtype 1a]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
	[[Category: Appleby, T C]]		[[Category: Appleby, T C]]

OCA at 05:48, 10 July 2019

2019-07-10T05:48:11Z

←Older revision		Revision as of 05:48, 10 July 2019
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 6nzv is ~~ON HOLD until Paper~~ Publication	+	==Crystal structure of HCV NS3/4A protease in complex with compound 12==
		+	<StructureSection load='6nzv' size='340' side='right'caption='[[6nzv]], [[Resolution\|resolution]] 1.55Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[6nzv]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6NZV OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6NZV FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=L9J:(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-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'>L9J</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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">[[6nzt\|6nzt]]</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=6nzv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6nzv OCA], [http://pdbe.org/6nzv PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6nzv RCSB], [http://www.ebi.ac.uk/pdbsum/6nzv PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6nzv ProSAT]</span></td></tr>
		+	</table>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Treatment of hepatitis C virus (HCV) infection has been historically challenging due the high viral genetic complexity wherein there are eight distinct genotypes and at least 86 viral subtypes. While HCV NS3/4A protease inhibitors are an established treatment option for genotype 1 infection, limited coverage of genotypes 2 and/or 3 combined with serum alanine transaminase (ALT) elevations for some compounds has limited the broad utility of this therapeutic class. Our discovery efforts were focused on identifying an NS3/4A protease inhibitor with pan-genotypic antiviral activity, improved coverage of resistance associated substitutions, and a decreased risk of hepatotoxicity. Towards this goal, distinct interactions with the conserved catalytic triad of the NS3/4A protease were identified that improved genotype 3 antiviral activity. We further discovered that protein adduct formation strongly correlated with clinical ALT elevation for this therapeutic class. Improving metabolic stability and decreasing protein adduct formation through structural modifications ultimately resulted in voxilaprevir. Voxilaprevir, in combination with sofosbuvir and velpatasvir, has demonstrated pan-genotypic antiviral clinical activity. Furthermore, hepatotoxicity was not observed in Phase 3 clinical trials with voxilaprevir, consistent with our design strategy. Vosevi((R)) (sofosbuvir, velpatasvir, and voxilaprevir) is now an approved pan-genotypic treatment option for the most difficult-to-cure individuals who have previously failed direct acting antiviral therapy.

-	~~Authors~~: ~~Appleby, T.C~~., Taylor, J.G.	+	Discovery of the pan-genotypic hepatitis C virus NS3/4A protease inhibitor voxilaprevir (GS-9857): A component of Vosevi((R)).,Taylor JG, Zipfel S, Ramey K, Vivian R, Schrier A, Karki KK, Katana A, Kato D, Kobayashi T, Martinez R, Sangi M, Siegel D, Tran CV, Yang ZY, Zablocki J, Yang CY, Wang Y, Wang K, Chan K, Barauskas O, Cheng G, Jin D, Schultz BE, Appleby T, Villasenor AG, Link JO Bioorg Med Chem Lett. 2019 Mar 26. pii: S0960-894X(19)30178-7. doi:, 10.1016/j.bmcl.2019.03.037. PMID:31133531<ref>PMID:31133531</ref>

-	~~Description: Crystal structure~~ of ~~HCV NS3~~/~~4A protease in complex with compound 12~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased~~ Structures]]	+	</div>
-	[[Category: Appleby, T.C]]	+	<div class="pdbe-citations 6nzv" style="background-color:#fffaf0;"></div>
-	[[Category: Taylor, J.G]]	+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Appleby, T C]]
		+	[[Category: Taylor, J G]]
		+	[[Category: Hepatitis c virus]]
		+	[[Category: Viral protease inhibitor]]
		+	[[Category: Viral protein]]
		+	[[Category: Viral protein-inhibitor complex]]
		+	[[Category: Voxilaprevir]]

OCA at 05:38, 6 March 2019

2019-03-06T05:38:31Z

←Older revision		Revision as of 05:38, 6 March 2019
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 6nzv is ON HOLD	+	The entry 6nzv is ON HOLD until Paper Publication

	Authors: Appleby, T.C., Taylor, J.G.		Authors: Appleby, T.C., Taylor, J.G.

OCA: Protected "6nzv" [edit=sysop:move=sysop]

2019-02-21T05:17:13Z

Protected "6nzv" [edit=sysop:move=sysop]

←Older revision

Revision as of 05:17, 21 February 2019

OCA: New page: '''Unreleased structure''' The entry 6nzv is ON HOLD Authors: Appleby, T.C., Taylor, J.G. Description: Crystal structure of HCV NS3/4A protease in complex with compound 12 [[Category: ...

2019-02-21T05:17:12Z

New page: '''Unreleased structure''' The entry 6nzv is ON HOLD Authors: Appleby, T.C., Taylor, J.G. Description: Crystal structure of HCV NS3/4A protease in complex with compound 12 [[Category: ...

New page

'''Unreleased structure'''

The entry 6nzv is ON HOLD

Authors: Appleby, T.C., Taylor, J.G.

Description: Crystal structure of HCV NS3/4A protease in complex with compound 12
[[Category: Unreleased Structures]]
[[Category: Appleby, T.C]]
[[Category: Taylor, J.G]]