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==Crystal structure of a genotype 1a/3a chimeric HCV NS3/4A protease in complex with danoprevir==
==Crystal structure of a genotype 1a/3a chimeric HCV NS3/4A protease in complex with danoprevir==
<StructureSection load='5eqr' size='340' side='right' caption='[[5eqr]], [[Resolution|resolution]] 1.96&Aring;' scene=''>
<StructureSection load='5eqr' size='340' side='right'caption='[[5eqr]], [[Resolution|resolution]] 1.96&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[5eqr]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5EQR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5EQR FirstGlance]. <br>
<table><tr><td colspan='2'>[[5eqr]] 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=5EQR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5EQR 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='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.96&#8491;</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5eqs|5eqs]], [[5eqq|5eqq]]</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='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=5eqr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5eqr OCA], [http://pdbe.org/5eqr PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5eqr RCSB], [http://www.ebi.ac.uk/pdbsum/5eqr PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5eqr ProSAT]</span></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=5eqr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5eqr OCA], [https://pdbe.org/5eqr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5eqr RCSB], [https://www.ebi.ac.uk/pdbsum/5eqr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5eqr ProSAT]</span></td></tr>
</table>
</table>
<div style="background-color:#fffaf0;">
== Function ==
== Publication Abstract from PubMed ==
[https://www.uniprot.org/uniprot/A0A0B4WYC6_9HEPC A0A0B4WYC6_9HEPC]
Hepatitis C virus (HCV), affecting an estimated 150 million people worldwide, is the leading cause of viral hepatitis, cirrhosis and hepatocellular carcinoma. HCV is genetically diverse with six genotypes (GTs) and multiple subtypes of different global distribution and prevalence. Recent development of direct-acting antivirals against HCV including NS3/4A protease inhibitors (PIs) has greatly improved treatment outcomes for GT-1. However, all current PIs exhibit significantly lower potency against GT-3. Lack of structural data on GT-3 protease has limited our ability to understand PI failure in GT-3. In this study the molecular basis for reduced potency of current inhibitors against GT-3 NS3/4A protease is elucidated with structure determination, molecular dynamics simulations and inhibition assays. A chimeric GT-1a3a NS3/4A protease amenable to crystallization was engineered to recapitulate decreased sensitivity of GT-3 protease to PIs. High-resolution crystal structures of this GT-1a3a bound to 3 PIs, asunaprevir, danoprevir and vaniprevir, had only subtle differences relative to GT-1 despite orders of magnitude loss in affinity. In contrast, hydrogen-bonding interactions within and with the protease active site and dynamic fluctuations of the PIs were drastically altered. The correlation between loss of intermolecular dynamics and inhibitor potency suggests a mechanism where polymorphisms between genotypes (or selected mutations) in the drug target confer resistance through altering the intermolecular dynamics of the protein-inhibitor complex.


Molecular and Dynamic Mechanism Underlying Drug Resistance in Genotype 3 Hepatitis C NS3/4A Protease.,Soumana DI, Kurt Yilmaz N, Ali A, Prachanronarong KL, Schiffer CA J Am Chem Soc. 2016 Sep 14;138(36):11850-9. doi: 10.1021/jacs.6b06454. Epub 2016 , Sep 2. PMID:27512818<ref>PMID:27512818</ref>
==See Also==
 
*[[Virus protease 3D structures|Virus protease 3D structures]]
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5eqr" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Ali, A]]
[[Category: Hepacivirus C]]
[[Category: Prachanronarong, K L]]
[[Category: Large Structures]]
[[Category: Schiffer, C A]]
[[Category: Ali A]]
[[Category: Soumana, D]]
[[Category: Prachanronarong KL]]
[[Category: Yilmaz, N K]]
[[Category: Schiffer CA]]
[[Category: Danoprevir]]
[[Category: Soumana D]]
[[Category: Drug resistance]]
[[Category: Yilmaz NK]]
[[Category: Genotype 3]]
[[Category: Hcv protease inhibitor]]
[[Category: Hydrolase]]
[[Category: Hydrolase-hydrolase inhibitor complex]]

Latest revision as of 15:29, 6 March 2024

Crystal structure of a genotype 1a/3a chimeric HCV NS3/4A protease in complex with danoprevirCrystal structure of a genotype 1a/3a chimeric HCV NS3/4A protease in complex with danoprevir

Structural highlights

5eqr is a 1 chain structure with sequence from Hepacivirus C. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.96Å
Ligands:, ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

A0A0B4WYC6_9HEPC

See Also

5eqr, resolution 1.96Å

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