Crystal Structure of the Hepatitis C Virus NS3 Protease Domain Complexed with a Synthetic NS4A Cofactor Peptide

• Published in: Cell 1996-10, Vol.87 (2), p.343-355
• Main Authors: Kim, J.L, Morgenstern, K.A, Lin, C, Fox, T, Dwyer, M.D, Landro, J.A, Chambers, S.P, Markland, W, Lepre, C.A, O'Malley, E.T, Harbeson, S.L, Rice, C.M, Murcko, M.A, Caron, P.R, Thomson, J.A
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Binding Sites; Crystallography, X-Ray; Enzyme Activation; Hepacivirus - enzymology; hepatitis C virus; Macromolecular Substances; Models, Molecular; Molecular Sequence Data; Protein Binding; Protein Conformation; Sequence Alignment; Substrate Specificity; Viral Nonstructural Proteins - metabolism; Viral Nonstructural Proteins - ultrastructure; Zinc
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/S0092-8674(00)81351-3

An estimated 1% of the global human population is infected by hepatitis C viruses (HCVs), and there are no broadly effective treatments for the debilitating progression of chronic hepatitis C. A serine protease located within the HCV NS3 protein processes the viral polyprotein at four specific sites and is considered essential for replication. Thus, it emerges as an attractive target for drug design. We report here the 2.5 Å resolution X-ray crystal structure of the NS3 protease domain complexed with a synthetic NS4A activator peptide. The protease has a chymotrypsin-like fold and features a tetrahedrally coordinated metal ion distal to the active site. The NS4A peptide intercalates within a β sheet of the enzyme core.