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==Crystal structure of NS3/4A protease variant D168A in complex with MK-5172==
==Crystal structure of NS3/4A protease variant D168A in complex with MK-5172==
<StructureSection load='3suf' size='340' side='right' caption='[[3suf]], [[Resolution|resolution]] 2.19&Aring;' scene=''>
<StructureSection load='3suf' size='340' side='right'caption='[[3suf]], [[Resolution|resolution]] 2.19&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[3suf]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Hepatitis_c_virus Hepatitis c virus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3SUF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3SUF FirstGlance]. <br>
<table><tr><td colspan='2'>[[3suf]] is a 4 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=3SUF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3SUF FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=SUE:(1AR,5S,8S,10R,22AR)-5-TERT-BUTYL-N-{(1R,2S)-1-[(CYCLOPROPYLSULFONYL)CARBAMOYL]-2-ETHENYLCYCLOPROPYL}-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'>SUE</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]] 2.19&#8491;</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3su3|3su3]], [[3su4|3su4]], [[3su5|3su5]], [[3su6|3su6]], [[3sud|3sud]], [[3sue|3sue]], [[3sug|3sug]], [[3sv6|3sv6]], [[3sv7|3sv7]], [[3sv8|3sv8]], [[3sv9|3sv9]]</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=SUE:(1AR,5S,8S,10R,22AR)-5-TERT-BUTYL-N-{(1R,2S)-1-[(CYCLOPROPYLSULFONYL)CARBAMOYL]-2-ETHENYLCYCLOPROPYL}-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'>SUE</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NS3-NS4A ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=11103 Hepatitis C virus])</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=3suf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3suf OCA], [https://pdbe.org/3suf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3suf RCSB], [https://www.ebi.ac.uk/pdbsum/3suf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3suf ProSAT]</span></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=3suf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3suf OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3suf RCSB], [http://www.ebi.ac.uk/pdbsum/3suf PDBsum]</span></td></tr>
</table>
</table>
<div style="background-color:#fffaf0;">
== Function ==
== Publication Abstract from PubMed ==
[https://www.uniprot.org/uniprot/A8DG50_9HEPC A8DG50_9HEPC]
Hepatitis C virus (HCV) infects over 170 million people worldwide and is the leading cause of chronic liver diseases, including cirrhosis, liver failure, and liver cancer. Available antiviral therapies cause severe side effects and are effective only for a subset of patients, though treatment outcomes have recently been improved by the combination therapy now including boceprevir and telaprevir, which inhibit the viral NS3/4A protease. Despite extensive efforts to develop more potent next-generation protease inhibitors, however, the long-term efficacy of this drug class is challenged by the rapid emergence of resistance. Single-site mutations at protease residues R155, A156 and D168 confer resistance to nearly all inhibitors in clinical development. Thus, developing the next-generation of drugs that retain activity against a broader spectrum of resistant viral variants requires a comprehensive understanding of the molecular basis of drug resistance. In this study, 16 high-resolution crystal structures of four representative protease inhibitors - telaprevir, danoprevir, vaniprevir and MK-5172 - in complex with the wild-type protease and three major drug-resistant variants R155K, A156T and D168A, reveal unique molecular underpinnings of resistance to each drug. The drugs exhibit differential susceptibilities to these protease variants in both enzymatic and antiviral assays. Telaprevir, danoprevir and vaniprevir interact directly with sites that confer resistance upon mutation, while MK-5172 interacts in a unique conformation with the catalytic triad. This novel mode of MK-5172 binding explains its retained potency against two multi-drug-resistant variants, R155K and D168A. These findings define the molecular basis of HCV N3/4A protease inhibitor resistance and provide potential strategies for designing robust therapies against this rapidly evolving virus.
 
The Molecular Basis of Drug Resistance against Hepatitis C Virus NS3/4A Protease Inhibitors.,Romano KP, Ali A, Aydin C, Soumana D, Ozen A, Deveau LM, Silver C, Cao H, Newton A, Petropoulos CJ, Huang W, Schiffer CA PLoS Pathog. 2012 Jul;8(7):e1002832. Epub 2012 Jul 26. PMID:22910833<ref>PMID:22910833</ref>


From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
==See Also==
</div>
*[[Virus protease 3D structures|Virus protease 3D structures]]
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Hepatitis c virus]]
[[Category: Hepatitis C virus genotype 1a]]
[[Category: Romano, K P]]
[[Category: Large Structures]]
[[Category: Schiffer, C A]]
[[Category: Romano KP]]
[[Category: Drug design]]
[[Category: Schiffer CA]]
[[Category: Drug resistance]]
[[Category: Hcv]]
[[Category: Hydrolase-inhibitor complex]]
[[Category: Protease inhibitor]]
[[Category: Serine protease]]
[[Category: Viral protein]]

Latest revision as of 12:57, 1 March 2024

Crystal structure of NS3/4A protease variant D168A in complex with MK-5172Crystal structure of NS3/4A protease variant D168A in complex with MK-5172

Structural highlights

3suf is a 4 chain structure with sequence from Hepatitis C virus genotype 1a. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.19Å
Ligands:, ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

A8DG50_9HEPC

See Also

3suf, resolution 2.19Å

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