Structural analysis of the SARS-CoV-2 methyltransferase complex involved in RNA cap creation bound to sinefungin

Nat Commun. 2020 Jul 24;11(1):3717. doi: 10.1038/s41467-020-17495-9.

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the COVID-19 pandemic. 2'-O-RNA methyltransferase (MTase) is one of the enzymes of this virus that is a potential target for antiviral therapy as it is crucial for RNA cap formation; an essential process for viral RNA stability. This MTase function is associated with the nsp16 protein, which requires a cofactor, nsp10, for its proper activity. Here we show the crystal structure of the nsp10-nsp16 complex bound to the pan-MTase inhibitor sinefungin in the active site. Our structural comparisons reveal low conservation of the MTase catalytic site between Zika and SARS-CoV-2 viruses, but high conservation of the MTase active site between SARS-CoV-2 and SARS-CoV viruses; these data suggest that the preparation of MTase inhibitors targeting several coronaviruses - but not flaviviruses - should be feasible. Together, our data add to important information for structure-based drug discovery.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / analogs & derivatives
  • Adenosine / metabolism
  • Adenosine / pharmacology
  • Betacoronavirus / enzymology*
  • COVID-19
  • Catalytic Domain
  • Coronavirus Infections / virology
  • Crystallography, X-Ray
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Methyltransferases / chemistry*
  • Methyltransferases / metabolism
  • Models, Chemical
  • Models, Molecular
  • Pandemics
  • Pneumonia, Viral / virology
  • RNA Caps
  • RNA Stability
  • RNA, Viral / metabolism
  • SARS-CoV-2
  • Viral Nonstructural Proteins / chemistry*
  • Viral Nonstructural Proteins / metabolism
  • Viral Regulatory and Accessory Proteins / chemistry*
  • Viral Regulatory and Accessory Proteins / metabolism

Substances

  • Enzyme Inhibitors
  • NSP10 protein, SARS-CoV-2
  • NSP16 protein, SARS-CoV-2
  • RNA Caps
  • RNA, Viral
  • Viral Nonstructural Proteins
  • Viral Regulatory and Accessory Proteins
  • Methyltransferases
  • RNA 2'-O-methyltransferase
  • Adenosine
  • sinefungin