4wh6: Difference between revisions
Jump to navigation
Jump to search
No edit summary |
No edit summary |
||
| (3 intermediate revisions by the same user not shown) | |||
| Line 1: | Line 1: | ||
==Crystal structure of HCV NS3/4A protease variant R155K in complex with Asunaprevir== | ==Crystal structure of HCV NS3/4A protease variant R155K in complex with Asunaprevir== | ||
<StructureSection load='4wh6' size='340' side='right' caption='[[4wh6]], [[Resolution|resolution]] 1.99Å' scene=''> | <StructureSection load='4wh6' size='340' side='right'caption='[[4wh6]], [[Resolution|resolution]] 1.99Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4wh6]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4WH6 OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[4wh6]] 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=4WH6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4WH6 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2R9:N-(TERT-BUTOXYCARBONYL)-3-METHYL-L-VALYL-(4R)-4-[(7-CHLORO-4-METHOXYISOQUINOLIN-1-YL)OXY]-N-{(1R,2S)-1-[(CYCLOPROPYLSULFONYL)CARBAMOYL]-2-ETHENYLCYCLOPROPYL}-L-PROLINAMIDE'>2R9</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.99Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2R9:N-(TERT-BUTOXYCARBONYL)-3-METHYL-L-VALYL-(4R)-4-[(7-CHLORO-4-METHOXYISOQUINOLIN-1-YL)OXY]-N-{(1R,2S)-1-[(CYCLOPROPYLSULFONYL)CARBAMOYL]-2-ETHENYLCYCLOPROPYL}-L-PROLINAMIDE'>2R9</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'>[ | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4wh6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4wh6 OCA], [https://pdbe.org/4wh6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4wh6 RCSB], [https://www.ebi.ac.uk/pdbsum/4wh6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4wh6 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | |||
[https://www.uniprot.org/uniprot/A8DG50_9HEPC A8DG50_9HEPC] | |||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
| Line 15: | Line 18: | ||
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 4wh6" 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: Hepatitis C virus genotype 1a]] | ||
[[Category: Large Structures]] | |||
[[Category: | [[Category: Ali A]] | ||
[[Category: | [[Category: Schiffer CA]] | ||
[[Category: | [[Category: Soumana DI]] | ||
[[Category: | |||
Latest revision as of 03:53, 28 December 2023
Crystal structure of HCV NS3/4A protease variant R155K in complex with AsunaprevirCrystal structure of HCV NS3/4A protease variant R155K in complex with Asunaprevir
Structural highlights
FunctionPublication Abstract from PubMedAsunaprevir (ASV), an isoquinoline-based competitive inhibitor targeting the hepatitis C virus (HCV) NS3/4A protease, is very potent in vivo. However, the potency is significantly compromised by the drug resistance mutations R155K and D168A. In this study three crystal structures of ASV and an analogue were determined to analyze the structural basis of drug resistance susceptibility. These structures revealed that ASV makes extensive contacts with Arg155 outside the substrate envelope. Arg155 in turn is stabilized by Asp168, and thus when either residue is mutated, the enzyme's interaction with ASV's P2* isoquinoline is disrupted. Adding a P1-P3 macrocycle to ASV enhances the inhibitor's resistance barrier, likely due to poising the inhibitor to its bound conformation. Macrocyclic inhibitors with P2* extension moieties avoiding interaction with the protease S2 residues including Arg155 must be chosen for future design of more robust protease inhibitors. Structural Analysis of Asunaprevir Resistance in HCV NS3/4A Protease.,Soumana DI, Ali A, Schiffer CA ACS Chem Biol. 2014 Sep 30. PMID:25243902[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
|
| ||||||||||||||||||