The solution structure of the N-terminal proteinase domain of the hepatitis C virus (HCV) NS3 protein provides new insights into its activation and catalytic mechanism

The solution structure of the hepatitis C virus (BK strain) NS3 protein N-t erminal domain (186 residues) has been solved by NMR spectroscopy. The prot ein is a serine protease with a chymotrypsin-type fold, and is involved in the maturation of the viral polyprotein. Despite the knowledge that its act ivity is enhanced by the action of a viral protein cofactor, NS4A, the mech anism of activation is not yet clear. The analysis of the folding in soluti on and the differences from the crystallographic structures allow the formu lation of a model in which, in addition to the NS4A cofactor, the substrate plays an important role in the activation of the catalytic mechanism. A un ique structural feature is the presence of a zinc-binding site exposed on t he surface, subject to a slow conformational exchange process. (C) 1999 Aca demic Press.