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| | ==Crystal Structure of Hepatitis C Virus NS3 Helicase Inhibitor Co-complex with Fragment 1 [(5-bromo-1H-indol-3-yl)acetic acid]== | | ==Crystal Structure of Hepatitis C Virus NS3 Helicase Inhibitor Co-complex with Fragment 1 [(5-bromo-1H-indol-3-yl)acetic acid]== |
| - | <StructureSection load='4ojq' size='340' side='right' caption='[[4ojq]], [[Resolution|resolution]] 2.25Å' scene=''> | + | <StructureSection load='4ojq' size='340' side='right'caption='[[4ojq]], [[Resolution|resolution]] 2.25Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4ojq]] is a 2 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=4OJQ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4OJQ FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4ojq]] is a 2 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=4OJQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4OJQ FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2SX:(5-BROMO-1H-INDOL-3-YL)ACETIC+ACID'>2SX</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</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]] 2.25Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4ok3|4ok3]], [[4ok5|4ok5]], [[4ok6|4ok6]], [[4oks|4oks]]</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2SX:(5-BROMO-1H-INDOL-3-YL)ACETIC+ACID'>2SX</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NS3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=11103 9HEPC])</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=4ojq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ojq OCA], [https://pdbe.org/4ojq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ojq RCSB], [https://www.ebi.ac.uk/pdbsum/4ojq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ojq ProSAT]</span></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=4ojq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ojq OCA], [http://pdbe.org/4ojq PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4ojq RCSB], [http://www.ebi.ac.uk/pdbsum/4ojq PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4ojq ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| - | <div style="background-color:#fffaf0;">
| + | == Function == |
| - | == Publication Abstract from PubMed == | + | [https://www.uniprot.org/uniprot/K4KA16_9HEPC K4KA16_9HEPC] |
| - | Future treatments for individuals infected by the hepatitis C virus (HCV) will likely involve combinations of compounds that inhibit multiple viral targets. The helicase of HCV is an attractive target with no known drug candidates in clinical trials. Herein we describe an integrated strategy for identifying fragment inhibitors using structural and biophysical techniques. Based on an X-ray structure of apo HCV helicase and in silico and bioinformatic analyses of HCV variants, we identified that one site in particular (labeled 3 + 4) was the most conserved and attractive pocket to target for a drug discovery campaign. Compounds from multiple sources were screened to identify inhibitors or binders to this site, and enzymatic and biophysical assays (NMR and SPR) were used to triage the most promising ligands for 3D structure determination by X-ray crystallography. Medicinal chemistry and biophysical evaluations focused on exploring the most promising lead series. The strategies employed here can have general utility in drug discovery.
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| - | Integrated strategies for identifying leads that target the NS3 helicase of the hepatitis C virus.,Laplante SR, Padyana AK, Abeywardane A, Bonneau P, Cartier M, Coulombe R, Jakalian A, Wildeson-Jones J, Li X, Liang S, McKercher G, White P, Zhang Q, Taylor SJ J Med Chem. 2014 Mar 13;57(5):2074-90. doi: 10.1021/jm401432c. Epub 2014 Jan 27. PMID:24467709<ref>PMID:24467709</ref>
| + | ==See Also== |
| - | | + | *[[Virus protease 3D structures|Virus protease 3D structures]] |
| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
| + | |
| - | </div>
| + | |
| - | <div class="pdbe-citations 4ojq" style="background-color:#fffaf0;"></div>
| + | |
| - | == References == | + | |
| - | <references/>
| + | |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Padyana, A K]] | + | [[Category: Hepacivirus C]] |
| - | [[Category: Atpase]] | + | [[Category: Large Structures]] |
| - | [[Category: Hepatitis]] | + | [[Category: Padyana AK]] |
| - | [[Category: Hydrolase-hydrolase inhibitor complex]]
| + | |
| - | [[Category: Ns3 helicase]]
| + | |
| - | [[Category: Ntpase]]
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