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Proc Natl Acad Sci U S A. 2018 Jan 9;115(2):E162-E171. doi: 10.1073/pnas.1718806115. Epub 2017 Dec 26.

Structural and molecular basis of mismatch correction and ribavirin excision from coronavirus RNA.

Author information

1
Centre National de la Recherche Scientifique, Aix-Marseille Université, CNRS UMR 7257, Architecture et Fonction des Macromolécules Biologiques, 13009 Marseille, France.
2
Global Phasing Ltd., Cambridge CB3 0AX, England.
3
Centre National de la Recherche Scientifique, Aix-Marseille Université, CNRS UMR 7257, Architecture et Fonction des Macromolécules Biologiques, 13009 Marseille, France; isabelle.imbert@univ-amu.fr.

Abstract

Coronaviruses (CoVs) stand out among RNA viruses because of their unusually large genomes (∼30 kb) associated with low mutation rates. CoVs code for nsp14, a bifunctional enzyme carrying RNA cap guanine N7-methyltransferase (MTase) and 3'-5' exoribonuclease (ExoN) activities. ExoN excises nucleotide mismatches at the RNA 3'-end in vitro, and its inactivation in vivo jeopardizes viral genetic stability. Here, we demonstrate for severe acute respiratory syndrome (SARS)-CoV an RNA synthesis and proofreading pathway through association of nsp14 with the low-fidelity nsp12 viral RNA polymerase. Through this pathway, the antiviral compound ribavirin 5'-monophosphate is significantly incorporated but also readily excised from RNA, which may explain its limited efficacy in vivo. The crystal structure at 3.38 Å resolution of SARS-CoV nsp14 in complex with its cofactor nsp10 adds to the uniqueness of CoVs among RNA viruses: The MTase domain presents a new fold that differs sharply from the canonical Rossmann fold.

KEYWORDS:

RNA virus; fold evolution; proofreading; ribavirin; virus replication

PMID:
29279395
PMCID:
PMC5777078
DOI:
10.1073/pnas.1718806115
[Indexed for MEDLINE]
Free PMC Article

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