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J. Biol. Chem., Vol. 275, Issue 33, 25523-25532, August 18, 2000
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From the We have constructed a structural model for
poliovirus RNA-dependent RNA polymerase
(3Dpol) in complex with a primer-template
(sym/sub) and ATP. Residues found in conserved structural motifs A
(Asp-238) and B (Asn-297) are involved in nucleotide selection. Asp-238
appears to couple binding of nucleotides with the correct sugar
configuration to catalytic efficiency at the active site of the enzyme.
Asn-297 is involved in selection of ribonucleoside triphosphates over 2'-dNTPs, a role mediated most likely via a hydrogen bond between the
side chain of this residue and the 2'-OH of the ribonucleoside triphosphate. Substitutions at position 238 or 297 of 3Dpol
produced derivatives exhibiting a range of catalytic efficiencies when
assayed in vitro for poly(rU) polymerase activity or
sym/sub elongation activity. A direct correlation existed between
activity on sym/sub and biological phenotypes; a 2.5-fold reduction in polymerase elongation rate produced virus with a temperature-sensitive growth phenotype. These data permit us to propose a detailed, structural model for nucleotide selection by 3Dpol, confirm
the biological relevance of the sym/sub system, and provide additional
evidence for kinetic coupling between RNA synthesis and subsequent
steps in the virus life cycle.
Poliovirus RNA-dependent RNA Polymerase
(3Dpol)
STRUCTURAL, BIOCHEMICAL, AND BIOLOGICAL ANALYSIS OF CONSERVED
STRUCTURAL MOTIFS A AND B*
§,
,,,**
Department of Biochemistry and Molecular
Biology, Pennsylvania State University, University Park, Pennsylvania
16802 and ¶ Department of Microbiology and Immunology, University
of California, San Francisco, California 94143
*
This work was supported in part by NCI, National Institutes
of Health (NIH), Howard Temin Award CA75118 (to C. E. C.) and NIAID,
NIH, Grants AI45818 (to C. E. C.) and AI40085 (to R. A.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Howard Hughes Medical Institute predoctoral fellow.
**
To whom correspondence should be addressed. Tel.: 814-863-8705;
Fax: 814-863-7024; E-mail: cec9@psu.edu.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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