Fidelity of Nucleotide Incorporation by the RNA-Dependent RNA Polymerase from Poliovirus

C. E. Cameron, I. M. Moustafa, J. J. Arnold

Research output: Chapter in Book/Report/Conference proceedingConference contribution

7 Scopus citations

Abstract

Using poliovirus (PV) and its RNA-dependent RNA polymerase (RdRp) as our primary model system, we have advanced knowledge fundamental to the chemistry and fidelity of nucleotide addition by nucleic acid polymerase. Two fidelity checkpoints exist prior to nucleotide addition. The first toggles the enzyme between a nucleotide binding-occluded state and a nucleotide binding-competent state. The second represents an ensemble of conformational states of conserved structural motifs that permits retention of the incoming nucleotide in a state competent for phosphoryl transfer long enough for chemistry to occur. Nucleophilic attack of the alpha-phosphorous atom of the incoming nucleotide produces a pentavalent transition state, collapse of which is facilitated by protonation of the pyrophosphate leaving group by a general acid. All of the relevant conformational states of the enzyme are controlled by a network of interacting residues that permits remote-site residues to control active-site function. The current state of the art for PV RdRp enzymology is such that mechanisms governing fidelity of this enzyme can now be targeted genetically and chemically for development of attenuated viruses and antiviral agents, respectively. Application of the knowledge obtained with the PV RdRp to the development of vaccines and antivirals for emerging RNA viruses represents an important goal for the future.

Original languageEnglish (US)
Title of host publicationDNA Replication Across Taxa, 2016
EditorsLaurie S. Kaguni, Marcos Tulio Oliveira
PublisherAcademic Press
Pages293-323
Number of pages31
ISBN (Print)9780128047354
DOIs
StatePublished - 2016

Publication series

NameEnzymes
Volume39
ISSN (Print)1874-6047

All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Biophysics
  • Biochemistry
  • Molecular Biology

Fingerprint Dive into the research topics of 'Fidelity of Nucleotide Incorporation by the RNA-Dependent RNA Polymerase from Poliovirus'. Together they form a unique fingerprint.

Cite this