CRYSTAL-STRUCTURE OF THE HEPATITIS-C VIRUS NS3 PROTEASE DOMAIN COMPLEXED WITH A SYNTHETIC NS4A COFACTOR PEPTIDE

An estimated 1% of the global human population is infected by hepatiti s 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 t he 2.5 Angstrom resolution X-ray crystal structure of the NS3 protease domain complexed with a synthetic NS4A activator peptide. The proteas e has a chymotrypsin-like fold and features a tetrahedrally coordinate d metal ion distal to the active site. The NS4A peptide intercalates w ithin a beta sheet of the enzyme core.