文摘
The NS3 protein of hepatitis C virus contains achymotrypsin-like serine proteinase domain.We built a homology model of this domain which predicts thepresence of a tetradentate metal bindingsite formed by three cysteines and one histidine. These residuesare strictly conserved in all knownhepatitis C viral genotypes as well as in other recently discoveredrelated hepatitis viruses. We show thatthe hepatitis C virus enzyme does indeed contain a Zn2+ion with S3N ligation and that the metal isrequired for structural integrity and activity of the enzyme.Strikingly, the residues forming the metalbinding site are also conserved in the chymotrypsin-like 2A cysteineproteinases of picornaviruses.Remarkably, in these highly variable viral genomes the metalbinding site is more conserved than thecatalytic residues and thus allows us to define a novel class of zincbinding chymotrypsin-like proteinasesand to identify a new attractive target for antiviraltherapy.