2fm2

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==HCV NS3-4A protease domain complexed with a ketoamide inhibitor, SCH446211==
==HCV NS3-4A protease domain complexed with a ketoamide inhibitor, SCH446211==
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<StructureSection load='2fm2' size='340' side='right' caption='[[2fm2]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
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<StructureSection load='2fm2' size='340' side='right'caption='[[2fm2]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[2fm2]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/9hepc 9hepc]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2FM2 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2FM2 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[2fm2]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Hepacivirus_C Hepacivirus C] and [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=2FM2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2FM2 FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3BC:TERT-BUTYL+[(1S)-1-({(1R,2S,5S)-2-[(3S,10S)-3-(CYCLOPROPYLMETHYL)-12-METHYL-4,5,8,11-TETRAOXO-10-PHENYL-2,6,9,12-TETRAAZATRIDECAN-1-OYL]-6,6-DIMETHYL-3-AZABICYCLO[3.1.0]HEX-3-YL}CARBONYL)-2,2-DIMETHYLPROPYL]CARBAMATE'>3BC</scene>, <scene name='pdbligand=BME:BETA-MERCAPTOETHANOL'>BME</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.7&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1a1r|1a1r]], [[1n1l|1n1l]], [[1rtl|1rtl]]</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3BC:TERT-BUTYL+[(1S)-1-({(1R,2S,5S)-2-[(3S,10S)-3-(CYCLOPROPYLMETHYL)-12-METHYL-4,5,8,11-TETRAOXO-10-PHENYL-2,6,9,12-TETRAAZATRIDECAN-1+-OYL]-6,6-DIMETHYL-3-AZABICYCLO[3.1.0]HEX-3-YL}CARBONYL)-2,2-DIMETHYLPROPYL]CARBAMATE'>3BC</scene>, <scene name='pdbligand=BME:BETA-MERCAPTOETHANOL'>BME</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NS polyprotein ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=11103 9HEPC])</td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2fm2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2fm2 OCA], [https://pdbe.org/2fm2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2fm2 RCSB], [https://www.ebi.ac.uk/pdbsum/2fm2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2fm2 ProSAT]</span></td></tr>
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<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=2fm2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2fm2 OCA], [http://pdbe.org/2fm2 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2fm2 RCSB], [http://www.ebi.ac.uk/pdbsum/2fm2 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2fm2 ProSAT]</span></td></tr>
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</table>
</table>
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<div style="background-color:#fffaf0;">
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== Function ==
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== Publication Abstract from PubMed ==
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[https://www.uniprot.org/uniprot/Q9ELS8_9HEPC Q9ELS8_9HEPC]
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Drug resistance is a major issue in the development and use of specific antiviral therapies. Here we report the isolation and characterization of hepatitis C virus RNA replicons resistant to a novel ketoamide inhibitor of the NS3/4A protease, SCH6 (originally SCH446211). Resistant replicon RNAs were generated by G418 selection in the presence of SCH6 in a dose-dependent fashion, with the emergence of resistance reduced at higher SCH6 concentrations. Sequencing demonstrated remarkable consistency in the mutations conferring SCH6 resistance in genotype 1b replicons derived from two different strains of hepatitis C virus, A156T/A156V and R109K. R109K, a novel mutation not reported previously to cause resistance to NS3/4A inhibitors, conferred moderate resistance only to SCH6. Structural analysis indicated that this reflects unique interactions of SCH6 with P'-side residues in the protease active site. In contrast, A156T conferred high level resistance to SCH6 and a related ketoamide, SCH503034, as well as BILN 2061 and VX-950. Unlike R109K, which had minimal impact on NS3/4A enzymatic function, A156T significantly reduced NS3/4A catalytic efficiency, polyprotein processing, and replicon fitness. However, three separate second-site mutations, P89L, Q86R, and G162R, were capable of partially reversing A156T-associated defects in polyprotein processing and/or replicon fitness, without significantly reducing resistance to the protease inhibitor.
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Mutations conferring resistance to SCH6, a novel hepatitis C virus NS3/4A protease inhibitor. Reduced RNA replication fitness and partial rescue by second-site mutations.,Yi M, Tong X, Skelton A, Chase R, Chen T, Prongay A, Bogen SL, Saksena AK, Njoroge FG, Veselenak RL, Pyles RB, Bourne N, Malcolm BA, Lemon SM J Biol Chem. 2006 Mar 24;281(12):8205-15. Epub 2005 Dec 13. PMID:16352601<ref>PMID:16352601</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 2fm2" style="background-color:#fffaf0;"></div>
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==See Also==
==See Also==
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*[[Helicase|Helicase]]
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*[[Helicase 3D structures|Helicase 3D structures]]
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== References ==
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*[[Virus protease 3D structures|Virus protease 3D structures]]
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<references/>
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Bogen, S L]]
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[[Category: Hepacivirus C]]
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[[Category: Bourne, N]]
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[[Category: Hepatitis C virus genotype 1a]]
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[[Category: Chase, R]]
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[[Category: Large Structures]]
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[[Category: Chen, T]]
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[[Category: Bogen SL]]
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[[Category: Lemon, S M]]
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[[Category: Bourne N]]
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[[Category: Malcolm, B A]]
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[[Category: Chase R]]
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[[Category: Njoroge, F G]]
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[[Category: Chen T]]
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[[Category: Prongay, A]]
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[[Category: Lemon SM]]
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[[Category: Pyles, R B]]
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[[Category: Malcolm BA]]
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[[Category: Saksena, A K]]
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[[Category: Njoroge FG]]
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[[Category: Skelton, A]]
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[[Category: Prongay A]]
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[[Category: Tong, X]]
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[[Category: Pyles RB]]
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[[Category: Veselenak, R L]]
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[[Category: Saksena AK]]
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[[Category: Yi, M]]
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[[Category: Skelton A]]
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[[Category: Hcv]]
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[[Category: Tong X]]
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[[Category: Hepatitis c virus]]
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[[Category: Veselenak RL]]
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[[Category: Hydrolase]]
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[[Category: Yi M]]
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[[Category: Ketoamide inhibitor]]
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[[Category: Ns3/4a protease]]
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Current revision

HCV NS3-4A protease domain complexed with a ketoamide inhibitor, SCH446211

PDB ID 2fm2

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