1RGQ

M9A HCV Protease complex with pentapeptide keto-amide inhibitor

Summary for 1RGQ

• Entry DOI: 10.2210/pdb1rgq/pdb
• Descriptor: NS3 Protease, NS4A peptide, ZINC ION, ... (4 entities in total)
• Functional Keywords: hepatitis c virus protease keto amide peptide inhibitor, viral protein, hydrolase
• Biological source: Hepatitis C virus; More
• Cellular location: Core protein p21: Host endoplasmic reticulum membrane; Single-pass membrane protein (By similarity). Core protein p19: Virion (By similarity). Envelope glycoprotein E1: Virion membrane; Single-pass type I membrane protein (Potential). Envelope glycoprotein E2: Virion membrane; Single-pass type I membrane protein (Potential). p7: Host endoplasmic reticulum membrane; Multi-pass membrane protein. Protease NS2-3: Host endoplasmic reticulum membrane; Multi-pass membrane protein (Potential). Serine protease NS3: Host endoplasmic reticulum membrane; Peripheral membrane protein (By similarity). Non-structural protein 4A: Host endoplasmic reticulum membrane; Single-pass type I membrane protein (Potential). Non-structural protein 4B: Host endoplasmic reticulum membrane; Multi-pass membrane protein. Non-structural protein 5A: Host endoplasmic reticulum membrane; Peripheral membrane protein. RNA-directed RNA polymerase: Host endoplasmic reticulum membrane; Single-pass type I membrane protein (Potential): P27958
• Total number of polymer chains: 4
• Total formula weight: 48076.96

Authors

Liu, Y.,Stoll, V.S.,Richardson, P.L.,Saldivar, A.,Klaus, J.L.,Molla, A.,Kohlbrenner, W.,Kati, W.M. (deposition date: 2003-11-12, release date: 2004-10-19, Last modification date: 2024-10-09)

Primary citation

Liu, Y.,Stoll, V.S.,Richardson, P.L.,Saldivar, A.,Klaus, J.L.,Molla, A.,Kohlbrenner, W.,Kati, W.M.
Hepatitis C NS3 protease inhibition by peptidyl-alpha-ketoamide inhibitors: kinetic mechanism and structure.
Arch.Biochem.Biophys., 421:207-216, 2004

PubMed Abstract: 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.

PubMed: 14984200
DOI: 10.1016/j.abb.2003.11.013

Experimental method

X-RAY DIFFRACTION (2.9 Å)