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© Research
Publication : The Journal of biological chemistry

Remote site control of an active site fidelity checkpoint in a viral RNA-dependent RNA polymerase

Scientific Fields
Diseases
Organisms
Applications
Technique

Published in The Journal of biological chemistry - 05 May 2005

Arnold JJ, Vignuzzi M, Stone JK, Andino R, Cameron CE

Link to Pubmed [PMID] – 15878882

J. Biol. Chem. 2005 Jul;280(27):25706-16

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 (3Dpol). 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.

http://www.ncbi.nlm.nih.gov/pubmed/15878882