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J. Biol. Chem., Vol. 280, Issue 27, 25706-25716, July 8, 2005

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Remote Site Control of an Active Site Fidelity Checkpoint in a Viral RNA-dependent RNA Polymerase^*

Jamie J. Arnold, Marco Vignuzzi, Jeffrey K. Stone, Raul Andino, and Craig E. Cameron, A recipient of an Established Investigator Award (0340028N) from the American Heart Association¶

From the Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, Pennsylvania 16802 and the Department of Microbiology and Immunology, University of California, San Francisco, California, 94143

The kinetic, thermodynamic, and structural basis for fidelity of nucleic acid polymerases remains controversial. An understanding of viral RNA-dependent RNA polymerase (RdRp) fidelity has become a topic of considerable interest as a result of recent experiments that show that a 2-fold increase in fidelity attenuates viral pathogenesis and a 2-fold decrease in fidelity reduces viral fitness. Here we show that a conformational change step preceding phosphoryl transfer is a key fidelity checkpoint for the poliovirus RdRp (3D^pol). We provide evidence that this conformational change step is orientation of the triphosphate into a conformation suitable for catalysis, suggesting a kinetic and structural model for RdRp fidelity that can be extrapolated to other classes of nucleic acid polymerases. Finally, we show that a site remote from the catalytic center can control this checkpoint, which occurs at the active site. Importantly, similar connections between a remote site and the active site exist in a wide variety of viral RdRps. The capacity for sites remote from the catalytic center to alter fidelity suggests new possibilities for targeting the viral RdRp for antiviral drug development.

Received for publication, March 30, 2005 , and in revised form, April 25, 2005.

^* This work was supported, in part, by Research Grants AI45818 (to C. E. C.) and AI40085 (to R. A.) from the National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802. Tel.: 814-863-8705; Fax: 814-865-7927; E-mail: cec9{at}psu.edu.

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