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==Crystal structure of HCV NS3/4A protease in complex with ITMN-191== | ==Crystal structure of HCV NS3/4A protease in complex with ITMN-191== | ||
<StructureSection load='3m5l' size='340' side='right' caption='[[3m5l]], [[Resolution|resolution]] 1.25Å' scene=''> | <StructureSection load='3m5l' size='340' side='right'caption='[[3m5l]], [[Resolution|resolution]] 1.25Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[3m5l]] is a 1 chain structure with sequence from [ | <table><tr><td colspan='2'>[[3m5l]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Hepatitis_c_virus_subtype_1a Hepatitis c virus subtype 1a]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3M5L OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3M5L 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=TSV:(2R,6S,12Z,13AS,14AR,16AS)-6-[(TERT-BUTOXYCARBONYL)AMINO]-14A-[(CYCLOPROPYLSULFONYL)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-2-YL+4-FLUORO-2H-ISOINDOLE-2-CARBOXYLATE'>TSV</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | </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=TSV:(2R,6S,12Z,13AS,14AR,16AS)-6-[(TERT-BUTOXYCARBONYL)AMINO]-14A-[(CYCLOPROPYLSULFONYL)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-2-YL+4-FLUORO-2H-ISOINDOLE-2-CARBOXYLATE'>TSV</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3m5m|3m5m]], [[3m5n|3m5n]], [[3m5o|3m5o]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3m5m|3m5m]], [[3m5n|3m5n]], [[3m5o|3m5o]]</div></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NS3 ([ | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NS3 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=31646 Hepatitis C virus subtype 1a])</td></tr> | ||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[ | <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'>[ | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3m5l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3m5l OCA], [https://pdbe.org/3m5l PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3m5l RCSB], [https://www.ebi.ac.uk/pdbsum/3m5l PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3m5l ProSAT]</span></td></tr> | ||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
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</div> | </div> | ||
<div class="pdbe-citations 3m5l" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 3m5l" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Virus protease 3D structures|Virus protease 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
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[[Category: Hepacivirin]] | [[Category: Hepacivirin]] | ||
[[Category: Hepatitis c virus subtype 1a]] | [[Category: Hepatitis c virus subtype 1a]] | ||
[[Category: Large Structures]] | |||
[[Category: Romano, K P]] | [[Category: Romano, K P]] | ||
[[Category: Schiffer, C A]] | [[Category: Schiffer, C A]] | ||
Revision as of 16:44, 4 May 2022
Crystal structure of HCV NS3/4A protease in complex with ITMN-191Crystal structure of HCV NS3/4A protease in complex with ITMN-191
Structural highlights
Publication Abstract from PubMedHepatitis C virus infects an estimated 180 million people worldwide, prompting enormous efforts to develop inhibitors targeting the essential NS3/4A protease. Resistance against the most promising protease inhibitors, telaprevir, boceprevir, and ITMN-191, has emerged in clinical trials. In this study, crystal structures of the NS3/4A protease domain reveal that viral substrates bind to the protease active site in a conserved manner defining a consensus volume, or substrate envelope. Mutations that confer the most severe resistance in the clinic occur where the inhibitors protrude from the substrate envelope, as these changes selectively weaken inhibitor binding without compromising the binding of substrates. These findings suggest a general model for predicting the susceptibility of protease inhibitors to resistance: drugs designed to fit within the substrate envelope will be less susceptible to resistance, as mutations affecting inhibitor binding would simultaneously interfere with the recognition of viral substrates. Drug resistance against HCV NS3/4A inhibitors is defined by the balance of substrate recognition versus inhibitor binding.,Romano KP, Ali A, Royer WE, Schiffer CA Proc Natl Acad Sci U S A. 2010 Dec 7;107(49):20986-91. Epub 2010 Nov 17. PMID:21084633[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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