3lox

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==HCV NS3-4a protease domain with a ketoamide inhibitor derivative of Boceprevir bound==
==HCV NS3-4a protease domain with a ketoamide inhibitor derivative of Boceprevir bound==
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<StructureSection load='3lox' size='340' side='right' caption='[[3lox]], [[Resolution|resolution]] 2.65&Aring;' scene=''>
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<StructureSection load='3lox' size='340' side='right'caption='[[3lox]], [[Resolution|resolution]] 2.65&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[3lox]] is a 4 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=3LOX OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3LOX FirstGlance]. <br>
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<table><tr><td colspan='2'>[[3lox]] 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=3LOX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3LOX 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=BME:BETA-MERCAPTOETHANOL'>BME</scene>, <scene name='pdbligand=MCX:(1R,2S,5S)-N-[(2S,3R)-4-AMINO-1-CYCLOBUTYL-3-HYDROXY-4-OXOBUTAN-2-YL]-6,6-DIMETHYL-3-{3-METHYL-N-[(1-METHYLCYCLOHEXYL)CARBAMOYL]-L-VALYL}-3-AZABICYCLO[3.1.0]HEXANE-2-CARBOXAMIDE'>MCX</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]] 2.65&#8491;</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=3lox FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3lox OCA], [http://pdbe.org/3lox PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3lox RCSB], [http://www.ebi.ac.uk/pdbsum/3lox PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3lox ProSAT]</span></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=BME:BETA-MERCAPTOETHANOL'>BME</scene>, <scene name='pdbligand=MCX:(1R,2S,5S)-N-[(2S,3R)-4-AMINO-1-CYCLOBUTYL-3-HYDROXY-4-OXOBUTAN-2-YL]-6,6-DIMETHYL-3-{3-METHYL-N-[(1-METHYLCYCLOHEXYL)CARBAMOYL]-L-VALYL}-3-AZABICYCLO[3.1.0]HEXANE-2-CARBOXAMIDE'>MCX</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'>[https://proteopedia.org/fgij/fg.htm?mol=3lox FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3lox OCA], [https://pdbe.org/3lox PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3lox RCSB], [https://www.ebi.ac.uk/pdbsum/3lox PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3lox 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/Q9ELS8_9HEPC Q9ELS8_9HEPC]
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In the search for a second generation HCV protease inhibitor, molecular modeling studies of the X-ray crystal structure of Boceprevir1 bound to the NS3 protein suggest that expansion into the S4 pocket could provide additional hydrophobic Van der Waals interactions. Effective replacement of the P4 tert-butyl with a cyclohexylmethyl ligand led to inhibitor 2 with improved enzyme and replicon activities. Subsequent modeling and SAR studies led to the pyridine 38 and sulfone analogues 52 and 53 with vastly improved PK parameters in monkeys, forming a new foundation for further exploration.
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The introduction of P4 substituted 1-methylcyclohexyl groups into Boceprevir: a change in direction in the search for a second generation HCV NS3 protease inhibitor.,Bennett F, Huang Y, Hendrata S, Lovey R, Bogen SL, Pan W, Guo Z, Prongay A, Chen KX, Arasappan A, Venkatraman S, Velazquez F, Nair L, Sannigrahi M, Tong X, Pichardo J, Cheng KC, Girijavallabhan VM, Saksena AK, Njoroge FG Bioorg Med Chem Lett. 2010 Apr 15;20(8):2617-21. Epub 2010 Feb 19. PMID:20303756<ref>PMID:20303756</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 3lox" style="background-color:#fffaf0;"></div>
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==See Also==
==See Also==
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*[[Proliferating Cell Nuclear Antigen|Proliferating Cell Nuclear Antigen]]
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*[[Proliferating cell nuclear antigen 3D structures|Proliferating cell nuclear antigen 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: Hepatitis c virus subtype 1a]]
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[[Category: Hepatitis C virus genotype 1a]]
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[[Category: Prongay, A J]]
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[[Category: Large Structures]]
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[[Category: Atp-binding]]
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[[Category: Prongay AJ]]
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[[Category: Hydrolase]]
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[[Category: Hydrolase-hydrolase inhibitor complex]]
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[[Category: Ketoamide inhibitor]]
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[[Category: Membrane]]
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[[Category: Ns3 protease domain]]
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[[Category: Nucleotide-binding]]
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[[Category: Rna replication]]
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[[Category: Serine protease]]
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[[Category: Transmembrane]]
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Current revision

HCV NS3-4a protease domain with a ketoamide inhibitor derivative of Boceprevir bound

PDB ID 3lox

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