4wh8
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | + | ==Crystal Structure of HCV NS3/4A protease in complex with an Asunaprevir P1-P3 macrocyclic analog.== | |
| + | <StructureSection load='4wh8' size='340' side='right'caption='[[4wh8]], [[Resolution|resolution]] 2.70Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[4wh8]] is a 2 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=4WH8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4WH8 FirstGlance]. <br> | ||
| + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.703Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3M7:TERT-BUTYL+[(2R,6S,12Z,13AS,14AR,16AS)-2-[(7-CHLORO-4-METHOXYISOQUINOLIN-1-YL)OXY]-14A-{[CYCLOPROPYL(DIHYDROXY)-LAMBDA~4~-SULFANYL]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'>3M7</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=4wh8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4wh8 OCA], [https://pdbe.org/4wh8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4wh8 RCSB], [https://www.ebi.ac.uk/pdbsum/4wh8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4wh8 ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/A8DG50_9HEPC A8DG50_9HEPC] | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Asunaprevir (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<ref>PMID:25243902</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| + | </div> | ||
| + | <div class="pdbe-citations 4wh8" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Hepatitis C virus genotype 1a]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Ali A]] | ||
| + | [[Category: Schiffer CA]] | ||
| + | [[Category: Soumana DI]] | ||
Current revision
Crystal Structure of HCV NS3/4A protease in complex with an Asunaprevir P1-P3 macrocyclic analog.
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