1rgq
From Proteopedia
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M9A HCV Protease complex with pentapeptide keto-amide inhibitor
Overview
A series of novel peptidyl-alpha-ketoamide compounds were evaluated as, inhibitors of the deltaNS3-NS4A serine protease from the hepatitis C, virus. These peptidyl-alpha-ketoamide inhibitors with Ki values ranging, from 0.17 nM to 5.6 microM exhibited slow-binding inhibition. Kinetic, studies established one-step kinetic mechanisms and dissociation rate, constants in the 3-7 x 10(-5) s(-1) range for these compounds. The, association rate constants, which ranged from 10 to 263,000 M(-1) s(-1), were responsible for the greater than four order of magnitude overall, binding affinity range exhibited by this series. An X-ray crystal, structure of a protease-inhibitor complex revealed an unusual interaction, between the oxyanion of the adduct and the protein as well as a, significant movement in the S1' region of the protein loop comprising, residues 35-42. These results are quite different from, peptidyl-alpha-ketoacid inhibition of HCV protease, which reportedly, undergoes no notable conformational changes and proceeds with a two-step, slow-binding kinetic mechanism.
About this Structure
1RGQ is a Protein complex structure of sequences from Hepatitis c virus with ZN and AKP as ligands. Active as Hepacivirin, with EC number 3.4.21.98 Full crystallographic information is available from OCA.
Reference
Hepatitis C NS3 protease inhibition by peptidyl-alpha-ketoamide inhibitors: kinetic mechanism and structure., Liu Y, Stoll VS, Richardson PL, Saldivar A, Klaus JL, Molla A, Kohlbrenner W, Kati WM, Arch Biochem Biophys. 2004 Jan 15;421(2):207-16. PMID:14984200
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