2oc8

Structure of Hepatitis C Viral NS3 protease domain complexed with NS4A peptide and ketoamide SCH503034

spinqualitylabelsall models 2oc8, resolution 2.66Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 2oc8 is a 4 chain structure with sequence from Hepatitis c virus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: BME, HU5, ZN Related: 2obo, 2oc1, 2oc0 Gene: NS3 (Hepatitis C virus) Resources: FirstGlance, OCA, RCSB, PDBsum Publication Abstract from PubMed The structures of both the native holo-HCV NS3/4A protease domain and the protease domain with a serine 139 to alanine (S139A) mutation were solved to high resolution. Subsequently, structures were determined for a series of ketoamide inhibitors in complex with the protease. The changes in the inhibitor potency were correlated with changes in the buried surface area upon binding the inhibitor to the active site. The largest contribution to the binding energy arises from the hydrophobic interactions of the P1 and P2 groups as they bind to the S1 and S2 pockets [the numbering of the subsites is as defined in Berger, A.; Schechter, I. Philos. Trans. R. Soc. London, Ser. B 1970, 257, 249-264]. This correlation of the changes in potency with increased buried surface area contributed directly to the design of a potent tripeptide inhibitor of the HCV NS3/4A protease that is currently in clinical trials. Discovery of the HCV NS3/4A protease inhibitor (1R,5S)-N-[3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3- [2(S)-[[[(1,1-dimethylethyl)amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl] - 6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2(S)-carboxamide (Sch 503034) II. Key steps in structure-based optimization.,Prongay AJ, Guo Z, Yao N, Pichardo J, Fischmann T, Strickland C, Myers J Jr, Weber PC, Beyer BM, Ingram R, Hong Z, Prosise WW, Ramanathan L, Taremi SS, Yarosh-Tomaine T, Zhang R, Senior M, Yang RS, Malcolm B, Arasappan A, Bennett F, Bogen SL, Chen K, Jao E, Liu YT, Lovey RG, Saksena AK, Venkatraman S, Girijavallabhan V, Njoroge FG, Madison V J Med Chem. 2007 May 17;50(10):2310-8. Epub 2007 Apr 20. PMID:17444623 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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