6cvw: Difference between revisions
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==Crystal structure of HCV NS3/4A WT protease in complex with AJ-52 (MK-5172 linear analogue)== | ==Crystal structure of HCV NS3/4A WT protease in complex with AJ-52 (MK-5172 linear analogue)== | ||
<StructureSection load='6cvw' size='340' side='right' caption='[[6cvw]], [[Resolution|resolution]] 1.78Å' scene=''> | <StructureSection load='6cvw' size='340' side='right'caption='[[6cvw]], [[Resolution|resolution]] 1.78Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[6cvw]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CVW OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[6cvw]] 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=6CVW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6CVW FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FH1:N-[(cyclopentyloxy)carbonyl]-3-methyl-L-valyl-(4R)-N-[(1R,2S)-2-ethenyl-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-4-[(7-methoxy-3-methylquinoxalin-2-yl)oxy]-L-prolinamide'>FH1</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]] 1.78Å</td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FH1:N-[(cyclopentyloxy)carbonyl]-3-methyl-L-valyl-(4R)-N-[(1R,2S)-2-ethenyl-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-4-[(7-methoxy-3-methylquinoxalin-2-yl)oxy]-L-prolinamide'>FH1</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'>[https://proteopedia.org/fgij/fg.htm?mol=6cvw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6cvw OCA], [https://pdbe.org/6cvw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6cvw RCSB], [https://www.ebi.ac.uk/pdbsum/6cvw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6cvw 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 == | ||
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</div> | </div> | ||
<div class="pdbe-citations 6cvw" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 6cvw" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Virus protease 3D structures|Virus protease 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Hepacivirus C]] | ||
[[Category: Large Structures]] | |||
[[Category: | [[Category: Matthew AN]] | ||
[[Category: | [[Category: Schiffer CA]] | ||
[[Category: | |||
Latest revision as of 18:11, 4 October 2023
Crystal structure of HCV NS3/4A WT protease in complex with AJ-52 (MK-5172 linear analogue)Crystal structure of HCV NS3/4A WT protease in complex with AJ-52 (MK-5172 linear analogue)
Structural highlights
FunctionPublication Abstract from PubMedA series of linear HCV NS3/4A protease inhibitors was designed by eliminating the P2-P4 macrocyclic linker in grazoprevir, which, in addition to conferring conformational flexibility, allowed structure-activity relationship (SAR) exploration of diverse quinoxalines at the P2 position. Biochemical and replicon data indicated preference for small hydrophobic groups at the 3-position of P2 quinoxaline for maintaining potency against resistant variants R155K, A156T, and D168A/V. The linear inhibitors, though generally less potent than the corresponding macrocyclic analogues, were relatively easier to synthesize and less susceptible to drug resistance. Three inhibitor cocrystal structures bound to wild-type NS3/4A protease revealed a conformation with subtle changes in the binding of P2 quinoxaline, depending on the 3-position substituent, likely impacting both inhibitor potency and resistance profile. The SAR and structural analysis highlight inhibitor features that strengthen interactions of the P2 moiety with the catalytic triad residues, providing valuable insights to improve potency against resistant variants. Quinoxaline-Based Linear HCV NS3/4A Protease Inhibitors Exhibit Potent Activity against Drug Resistant Variants.,Rusere LN, Matthew AN, Lockbaum GJ, Jahangir M, Newton A, Petropoulos CJ, Huang W, Kurt Yilmaz N, Schiffer CA, Ali A ACS Med Chem Lett. 2018 May 17;9(7):691-696. doi: 10.1021/acsmedchemlett.8b00150., eCollection 2018 Jul 12. PMID:30034602[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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