Structural basis of RNA cap modification by SARS-CoV-2

Nat Commun. 2020 Jul 24;11(1):3718. doi: 10.1038/s41467-020-17496-8.

Abstract

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of COVID-19 illness, has caused millions of infections worldwide. In SARS coronaviruses, the non-structural protein 16 (nsp16), in conjunction with nsp10, methylates the 5'-end of virally encoded mRNAs to mimic cellular mRNAs, thus protecting the virus from host innate immune restriction. We report here the high-resolution structure of a ternary complex of SARS-CoV-2 nsp16 and nsp10 in the presence of cognate RNA substrate analogue and methyl donor, S-adenosyl methionine (SAM). The nsp16/nsp10 heterodimer is captured in the act of 2'-O methylation of the ribose sugar of the first nucleotide of SARS-CoV-2 mRNA. We observe large conformational changes associated with substrate binding as the enzyme transitions from a binary to a ternary state. This induced fit model provides mechanistic insights into the 2'-O methylation of the viral mRNA cap. We also discover a distant (25 Å) ligand-binding site unique to SARS-CoV-2, which can alternatively be targeted, in addition to RNA cap and SAM pockets, for antiviral development.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Betacoronavirus
  • COVID-19
  • Coronavirus Infections / virology
  • Humans
  • Methyltransferases / chemistry*
  • Methyltransferases / metabolism
  • Models, Chemical
  • Models, Molecular
  • Pandemics
  • Pneumonia, Viral / virology
  • RNA Caps / metabolism*
  • RNA, Viral / metabolism
  • S-Adenosylmethionine / metabolism
  • SARS-CoV-2
  • Viral Nonstructural Proteins / chemistry*
  • Viral Nonstructural Proteins / metabolism
  • Viral Regulatory and Accessory Proteins / chemistry*
  • Viral Regulatory and Accessory Proteins / metabolism
  • X-Ray Diffraction

Substances

  • NSP10 protein, SARS-CoV-2
  • NSP16 protein, SARS-CoV-2
  • RNA Caps
  • RNA, Viral
  • Viral Nonstructural Proteins
  • Viral Regulatory and Accessory Proteins
  • S-Adenosylmethionine
  • Methyltransferases
  • RNA 2'-O-methyltransferase