Crystal structure of the RNA-dependent RNA polymerase of hepatitis C virus

We report the crystal structure of the RNA-dependent RNA polymerase of hepa titis C virus, a major human pathogen, to 2.8-Angstrom resolution. This enz yme is a key target for developing specific antiviral therapy. The structur e of the catalytic domain contains 531 residues folded in the characteristi c fingers, palm, and thumb subdomains. The fingers subdomain contains a reg ion, the "fingertips," that shares the same fold with reverse transcriptase s. Superposition to the available structures of the latter shows that resid ues from the palm and fingertips are structurally equivalent. In addition, it shows that the hepatitis C virus polymerase was crystallized in a closed fingers conformation, similar to HIV-1 reverse transcriptase in ternary co mplex with DNA and dTTP [Huang H., Chopra, R., Verdine, G. L. & Harrison, S . C. (1998) Science 282, 1669-1675]. This superposition reveals the majorit y of the amino acid residues of the hepatitis C virus enzyme that are likel y to be implicated in binding to the replicating RNA molecule and to the in coming NTP. It also suggests a rearrangement of the thumb domain as well as a possible concerted movement of thumb and fingertips during translocation of the RNA template-primer in successive polymerization rounds.