A ZINC-BINDING SITE IN VIRAL SERINE PROTEINASES

The NS3 protein of hepatitis C virus contains a chymotrypsin-like seri ne proteinase domain. We built a homology model of this domain which p redicts the presence of a tetradentate metal binding site formed by th ree cysteines and one histidine. These residues are strictly conserved in all known hepatitis C viral genotypes as well as in other recently discovered related hepatitis viruses, We show that the hepatitis C vi rus enzyme does indeed contain a Zn2+ ion with S3N ligation and that t he metal is required for structural integrity and activity of the enzy me, Strikingly, the residues farming the metal binding site are also c onserved in the chymotrypsin-like 2A cysteine proteinases of picornavi ruses. Remarkably, in these highly variable viral genomes the metal bi nding site is more conserved than the catalytic residues and thus allo ws us to define a novel class of zinc binding chymotrypsin-like protei nases and to identify a new attractive target for antiviral therapy.