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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / metabolism
  • Antiviral Agents / pharmacology
  • Coronavirus / drug effects
  • Coronavirus / genetics
  • Coronavirus / metabolism*
  • Crystallography, X-Ray
  • Exoribonucleases / chemistry
  • Exoribonucleases / genetics
  • Exoribonucleases / metabolism
  • Humans
  • Methyltransferases / chemistry
  • Methyltransferases / genetics
  • Methyltransferases / metabolism
  • Models, Molecular
  • Protein Binding
  • Protein Domains
  • RNA, Viral / genetics
  • RNA, Viral / metabolism*
  • Ribavirin / metabolism*
  • Ribavirin / pharmacology
  • Severe Acute Respiratory Syndrome / virology
  • Viral Nonstructural Proteins / chemistry
  • Viral Nonstructural Proteins / genetics
  • Viral Nonstructural Proteins / metabolism
  • Virus Replication*


  • Antiviral Agents
  • Nsp10 protein, SARS virus
  • RNA, Viral
  • Viral Nonstructural Proteins
  • Ribavirin
  • Methyltransferases
  • nsp14 protein, SARS coronavirus
  • Exoribonucleases

Associated data

  • PDB/5NFY