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Journal of Virology, April 2002, p. 3482-3492, Vol. 76, No. 7
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.7.3482-3492.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Structural Analysis of the Hepatitis C Virus RNA Polymerase in Complex with Ribonucleotides

Stéphane Bressanelli,1 Licia Tomei,2 Félix A. Rey,1* and Raffaele De Francesco2

Laboratoire de Virologie Moléculaire Structurale, Génétique des Virus, UMR 1157, CNRS-INRA, F-91198 Gif-sur-Yvette Cedex, France,1 Department of Biochemistry, Istituto di Ricerche di Biologia Molecolare "P. Angeletti," I-00040 Pomezia (Rome), Italy2

Received 6 September 2001/ Accepted 12 December 2001

We report here the results of a systematic high-resolution X-ray crystallographic analysis of complexes of the hepatitis C virus (HCV) RNA polymerase with ribonucleoside triphosphates (rNTPs) and divalent metal ions. An unexpected observation revealed by this study is the existence of a specific rGTP binding site in a shallow pocket at the molecular surface of the enzyme, 30 Å away from the catalytic site. This previously unidentified rGTP pocket, which lies at the interface between fingers and thumb, may be an allosteric regulatory site and could play a role in allowing alternative interactions between the two domains during a possible conformational change of the enzyme required for efficient initiation. The electron density map at 1.7-Å resolution clearly shows the mode of binding of the guanosine moiety to the enzyme. In the catalytic site, density corresponding to the triphosphates of nucleotides bound to the catalytic metals was apparent in each complex with nucleotides. Moreover, a network of triphosphate densities was detected; these densities superpose to the corresponding moieties of the nucleotides observed in the initiation complex reported for the polymerase of bacteriophage {phi}6, strengthening the proposal that the two enzymes initiate replication de novo by similar mechanisms. No equivalent of the protein stacking platform observed for the priming nucleotide in the {phi}6 enzyme is present in HCV polymerase, however, again suggesting that a change in conformation of the thumb domain takes place upon template binding to allow for efficient de novo initiation of RNA synthesis.

* Corresponding author. Mailing address: Laboratoire de Virologie Moléculaire Structurale, UMR 1157, CNRS-INRA, 1 Ave. de la Terrasse, F-91198 Gif-sur-Yvette Cedex, France. Phone: 33-169 823 844. Fax: 33-169 824 308. E-mail: rey{at}gv.cnrs-gif.fr.

Journal of Virology, April 2002, p. 3482-3492, Vol. 76, No. 7
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.7.3482-3492.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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