4nwk

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<StructureSection load='4nwk' size='340' side='right'caption='[[4nwk]], [[Resolution|resolution]] 1.62&Aring;' scene=''>
<StructureSection load='4nwk' size='340' side='right'caption='[[4nwk]], [[Resolution|resolution]] 1.62&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[4nwk]] is a 1 chain structure with sequence from [http://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=4NWK OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4NWK FirstGlance]. <br>
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<table><tr><td colspan='2'>[[4nwk]] is a 1 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=4NWK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4NWK 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=2R8:N-(TERT-BUTOXYCARBONYL)-3-METHYL-L-VALYL-(4R)-N-{(1R,2S)-1-[(CYCLOPROPYLSULFONYL)CARBAMOYL]-2-ETHENYLCYCLOPROPYL}-4-[(6-METHOXYISOQUINOLIN-1-YL)OXY]-L-PROLINAMIDE'>2R8</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 1.62&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4nwl|4nwl]]</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=2R8:N-(TERT-BUTOXYCARBONYL)-3-METHYL-L-VALYL-(4R)-N-{(1R,2S)-1-[(CYCLOPROPYLSULFONYL)CARBAMOYL]-2-ETHENYLCYCLOPROPYL}-4-[(6-METHOXYISOQUINOLIN-1-YL)OXY]-L-PROLINAMIDE'>2R8</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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=4nwk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4nwk OCA], [http://pdbe.org/4nwk PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4nwk RCSB], [http://www.ebi.ac.uk/pdbsum/4nwk PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4nwk ProSAT]</span></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=4nwk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4nwk OCA], [https://pdbe.org/4nwk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4nwk RCSB], [https://www.ebi.ac.uk/pdbsum/4nwk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4nwk ProSAT]</span></td></tr>
</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/A8DG50_9HEPC A8DG50_9HEPC]
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The discovery of BMS-605339 (35), a tripeptidic inhibitor of the NS3/4A enzyme, is described. This compound incorporates a cyclopropylacylsulfonamide moiety that was designed to improve the potency of carboxylic acid prototypes through the introduction of favorable nonbonding interactions within the S1' site of the protease. The identification of 35 was enabled through the optimization and balance of critical properties including potency and pharmacokinetics (PK). This was achieved through modulation of the P2* subsite of the inhibitor which identified the isoquinoline ring system as a key template for improving PK properties with further optimization achieved through functionalization. A methoxy moiety at the C6 position of this isoquinoline ring system proved to be optimal with respect to potency and PK, thus providing the clinical compound 35 which demonstrated antiviral activity in HCV-infected patients.
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Discovery and Early Clinical Evaluation of BMS-605339, a Potent and Orally Efficacious Tripeptidic Acylsulfonamide NS3 Protease Inhibitor for the Treatment of Hepatitis C Virus Infection.,Scola PM, Wang AX, Good AC, Sun LQ, Combrink KD, Campbell JA, Chen J, Tu Y, Sin N, Venables BL, Sit SY, Chen Y, Cocuzza A, Bilder DM, D'Andrea S, Zheng B, Hewawasam P, Ding M, Thuring J, Li J, Hernandez D, Yu F, Falk P, Zhai G, Sheaffer AK, Chen C, Lee MS, Barry D, Knipe JO, Li W, Han YH, Jenkins S, Gesenberg C, Gao Q, Sinz MW, Santone KS, Zvyaga T, Rajamani R, Klei HE, Colonno RJ, Grasela DM, Hughes E, Chien C, Adams S, Levesque PC, Li D, Zhu J, Meanwell NA, McPhee F J Med Chem. 2014 Mar 13;57(5):1708-29. doi: 10.1021/jm401840s. Epub 2014 Feb 20. PMID:24555570<ref>PMID:24555570</ref>
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==See Also==
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*[[Virus protease 3D structures|Virus protease 3D structures]]
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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 4nwk" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Hepatitis c virus subtype 1a]]
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[[Category: Hepatitis C virus genotype 1a]]
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Klei, H E]]
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[[Category: Klei HE]]
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[[Category: Muckelbauer, J K]]
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[[Category: Muckelbauer JK]]
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[[Category: Hydrolase-hydrolase inhibitor complex]]
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[[Category: Hydrolase/hydrolase inhibitor]]
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[[Category: Serine protease]]
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Current revision

Crystal structure of hepatis c virus protease (ns3) complexed with bms-605339 aka n-(tert-butoxycarbonyl)-3-me thyl-l-valyl-(4r)-n-((1r,2s)-1-((cyclopropylsulfonyl)carba moyl)-2-vinylcyclopropyl)-4-((6-methoxy-1-isoquinolinyl)ox y)-l-prolinamide

PDB ID 4nwk

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Proteopedia Page Contributors and Editors (what is this?)

OCA

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