Disclosed is an ATPase-deficient dominant-negative mutant NS3 protein of hepatitis C virus inhibits activity of the wild-type NS3 protein and inhibits replication of hepatitis C virus (HCV). The solved crystal structure of a multi-enzyme NS3 complex on a DNA substrate is also provided. Also provided is a method of inhibiting HCV replication in cells infected with HCV involving administering to the cells a dominant-negative mutant NS3 protein. Also, it provides peptides and agents that inhibit HCV replication and methods of identifying agents that inhibit HCV replication
