7mmi - Revision history

OCA at 16:16, 18 October 2023

2023-10-18T16:16:07Z

←Older revision		Revision as of 16:16, 18 October 2023
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	<StructureSection load='7mmi' size='340' side='right'caption='[[7mmi]], [[Resolution\|resolution]] 1.80Å' scene=''>		<StructureSection load='7mmi' size='340' side='right'caption='[[7mmi]], [[Resolution\|resolution]] 1.80Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[7mmi]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7MMI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7MMI FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[7mmi]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Hepacivirus_C Hepacivirus C]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7MMI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7MMI FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ZJV:(2S)-1,1,1-trifluoropropan-2-yl+{(2R,4S,6S,12Z,13aS,14aR,16aS)-2-[(7-methoxy-3-methylquinoxalin-2-yl)oxy]-14a-[(1-methylcyclopropane-1-sulfonyl)carbamoyl]-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl}carbamate'>ZJV</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]] 1.8Å</td></tr>
-	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Hepacivirin Hepacivirin], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.98 3.4.21.98] </span></td></tr>	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ZJV:(2S)-1,1,1-trifluoropropan-2-yl+{(2R,4S,6S,12Z,13aS,14aR,16aS)-2-[(7-methoxy-3-methylquinoxalin-2-yl)oxy]-14a-[(1-methylcyclopropane-1-sulfonyl)carbamoyl]-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl}carbamate'>ZJV</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'>[https://proteopedia.org/fgij/fg.htm?mol=7mmi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7mmi OCA], [https://pdbe.org/7mmi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7mmi RCSB], [https://www.ebi.ac.uk/pdbsum/7mmi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7mmi 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=7mmi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7mmi OCA], [https://pdbe.org/7mmi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7mmi RCSB], [https://www.ebi.ac.uk/pdbsum/7mmi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7mmi ProSAT]</span></td></tr>
	</table>		</table>
		+	== Function ==
		+	[https://www.uniprot.org/uniprot/A0A0B4WYC6_9HEPC A0A0B4WYC6_9HEPC]
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 21:		Line 23:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Hepacivirin~~]]	+	[[Category: Hepacivirus C]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Schiffer~~, C A~~]]	+	[[Category: Schiffer CA]]
-	[[Category: Zephyr, J]]	+	[[Category: Zephyr J]]
-	~~[[Category: Drug resistance]]~~	+
-	~~[[Category: Hepatitis c virus]]~~	+
-	~~[[Category: Hydrolase-inhibitor complex]]~~	+
-	~~[[Category: Ns3/4a protease]]~~	+
-	~~[[Category: Protease inhibitor~~]]	+

OCA at 11:14, 30 March 2022

2022-03-30T11:14:20Z

←Older revision		Revision as of 11:14, 30 March 2022
Line 1:		Line 1:

	==Crystal structure of HCV NS3/4A D168A protease in complex with NR02-23==		==Crystal structure of HCV NS3/4A D168A protease in complex with NR02-23==
-	<StructureSection load='7mmi' size='340' side='right'caption='[[7mmi]]' scene=''>	+	<StructureSection load='7mmi' size='340' side='right'caption='[[7mmi]], [[Resolution\|resolution]] 1.80Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7MMI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7MMI FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[7mmi]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7MMI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7MMI FirstGlance]. <br>
-	</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=7mmi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7mmi OCA], [https://pdbe.org/7mmi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7mmi RCSB], [https://www.ebi.ac.uk/pdbsum/7mmi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7mmi ProSAT]</span></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ZJV:(2S)-1,1,1-trifluoropropan-2-yl+{(2R,4S,6S,12Z,13aS,14aR,16aS)-2-[(7-methoxy-3-methylquinoxalin-2-yl)oxy]-14a-[(1-methylcyclopropane-1-sulfonyl)carbamoyl]-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl}carbamate'>ZJV</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
		+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Hepacivirin Hepacivirin], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.98 3.4.21.98] </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=7mmi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7mmi OCA], [https://pdbe.org/7mmi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7mmi RCSB], [https://www.ebi.ac.uk/pdbsum/7mmi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7mmi ProSAT]</span></td></tr>
	</table>		</table>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Third generation Hepatitis C virus (HCV) NS3/4A protease inhibitors (PIs), glecaprevir and voxilaprevir, are highly effective across genotypes and against many resistant variants. Unlike earlier PIs, these compounds have fluorine substitutions on the P2-P4 macrocycle and P1 moieties. Fluorination has long been used in medicinal chemistry as a strategy to improve physicochemical properties and potency. However, the molecular basis by which fluorination improves potency and resistance profile of HCV NS3/4A PIs is not well understood. To systematically analyze the contribution of fluorine substitutions to inhibitor potency and resistance profile, we used a multi-disciplinary approach involving inhibitor design and synthesis, enzyme inhibition assays, co-crystallography, and structural analysis. A panel of inhibitors in matched pairs were designed with and without P4 cap fluorination, tested against WT protease and the D168A resistant variant, and a total of 22 high-resolution co-crystal structures were determined. While fluorination did not significantly improve potency against the WT protease, PIs with fluorinated P4 caps retained much better potency against the D168A protease variant. Detailed analysis of the co-crystal structures revealed that PIs with fluorinated P4 caps can sample alternate binding conformations that enable adapting to structural changes induced by the D168A substitution. Our results elucidate molecular mechanisms of fluorine-specific inhibitor interactions that can be leveraged in avoiding drug resistance.
		+
		+	Deciphering the Molecular Mechanism of HCV Protease Inhibitor Fluorination as a General Approach to Avoid Drug Resistance.,Zephyr J, Nageswara Rao D, Vo SV, Henes M, Kosovrasti K, Matthew AN, Hedger AK, Timm J, Chan ET, Ali A, Kurt Yilmaz N, Schiffer CA J Mol Biol. 2022 Feb 17:167503. doi: 10.1016/j.jmb.2022.167503. PMID:35183560<ref>PMID:35183560</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 7mmi" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Hepacivirin]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Schiffer CA]]	+	[[Category: Schiffer, C A]]
-	[[Category: Zephyr J]]	+	[[Category: Zephyr, J]]
		+	[[Category: Drug resistance]]
		+	[[Category: Hepatitis c virus]]
		+	[[Category: Hydrolase-inhibitor complex]]
		+	[[Category: Ns3/4a protease]]
		+	[[Category: Protease inhibitor]]

OCA at 06:05, 9 March 2022

2022-03-09T06:05:55Z

←Older revision		Revision as of 06:05, 9 March 2022
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry 7mmi is ON HOLD until Paper Publication~~	+	==Crystal structure of HCV NS3/4A D168A protease in complex with NR02-23==
-		+	<StructureSection load='7mmi' size='340' side='right'caption='[[7mmi]]' scene=''>
-	~~Authors: Zephyr, J., Schiffer, C.A.~~	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7MMI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7MMI FirstGlance]. <br>
-	~~Description:~~ Crystal structure of HCV NS3/4A D168A protease in complex with NR02-23	+	</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=7mmi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7mmi OCA], [https://pdbe.org/7mmi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7mmi RCSB], [https://www.ebi.ac.uk/pdbsum/7mmi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7mmi ProSAT]</span></td></tr>
-	[[Category: ~~Unreleased~~ Structures]]	+	</table>
-	[[Category: Schiffer~~, C.A~~]]	+	__TOC__
-	[[Category: Zephyr, J]]	+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Schiffer CA]]
		+	[[Category: Zephyr J]]

OCA at 07:55, 26 May 2021

2021-05-26T07:55:49Z

←Older revision		Revision as of 07:55, 26 May 2021
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 7mmi is ON HOLD	+	The entry 7mmi is ON HOLD until Paper Publication

	Authors: Zephyr, J., Schiffer, C.A.		Authors: Zephyr, J., Schiffer, C.A.

OCA: Protected "7mmi" [edit=sysop:move=sysop]

2021-05-05T07:31:41Z

Protected "7mmi" [edit=sysop:move=sysop]

←Older revision

Revision as of 07:31, 5 May 2021

OCA: New page: '''Unreleased structure''' The entry 7mmi is ON HOLD Authors: Zephyr, J., Schiffer, C.A. Description: Crystal structure of HCV NS3/4A D168A protease in complex with NR02-23 [[Category:...

2021-05-05T07:31:40Z

New page: '''Unreleased structure''' The entry 7mmi is ON HOLD Authors: Zephyr, J., Schiffer, C.A. Description: Crystal structure of HCV NS3/4A D168A protease in complex with NR02-23 [[Category:...

New page

'''Unreleased structure'''

The entry 7mmi is ON HOLD

Authors: Zephyr, J., Schiffer, C.A.

Description: Crystal structure of HCV NS3/4A D168A protease in complex with NR02-23
[[Category: Unreleased Structures]]
[[Category: Schiffer, C.A]]
[[Category: Zephyr, J]]