Structural Basis for RNA Replication by the SARS-CoV-2 Polymerase

Cell. 2020 Jul 23;182(2):417-428.e13. doi: 10.1016/j.cell.2020.05.034. Epub 2020 May 22.


Nucleotide analog inhibitors, including broad-spectrum remdesivir and favipiravir, have shown promise in in vitro assays and some clinical studies for COVID-19 treatment, this despite an incomplete mechanistic understanding of the viral RNA-dependent RNA polymerase nsp12 drug interactions. Here, we examine the molecular basis of SARS-CoV-2 RNA replication by determining the cryo-EM structures of the stalled pre- and post- translocated polymerase complexes. Compared with the apo complex, the structures show notable structural rearrangements happening to nsp12 and its co-factors nsp7 and nsp8 to accommodate the nucleic acid, whereas there are highly conserved residues in nsp12, positioning the template and primer for an in-line attack on the incoming nucleotide. Furthermore, we investigate the inhibition mechanism of the triphosphate metabolite of remdesivir through structural and kinetic analyses. A transition model from the nsp7-nsp8 hexadecameric primase complex to the nsp12-nsp7-nsp8 polymerase complex is also proposed to provide clues for the understanding of the coronavirus transcription and replication machinery.

Keywords: 2019-nCoV; COVID-19; RdRP; SARS-CoV-2; favipiravir; nsp12; nsp8; polymerase; remdesivir; virus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Monophosphate / analogs & derivatives
  • Adenosine Monophosphate / chemistry
  • Adenosine Monophosphate / metabolism
  • Adenosine Monophosphate / pharmacology
  • Alanine / analogs & derivatives
  • Alanine / chemistry
  • Alanine / metabolism
  • Alanine / pharmacology
  • Antiviral Agents / chemistry
  • Antiviral Agents / metabolism
  • Antiviral Agents / pharmacology
  • Betacoronavirus / chemistry*
  • Betacoronavirus / enzymology*
  • Catalytic Domain
  • Coronavirus RNA-Dependent RNA Polymerase
  • Cryoelectron Microscopy
  • Models, Chemical
  • Models, Molecular
  • RNA, Viral / metabolism
  • RNA-Dependent RNA Polymerase / chemistry*
  • SARS-CoV-2
  • Transcription, Genetic
  • Viral Nonstructural Proteins / chemistry*
  • Virus Replication


  • Antiviral Agents
  • NS8 protein, SARS-CoV-2
  • RNA, Viral
  • Viral Nonstructural Proteins
  • remdesivir
  • Adenosine Monophosphate
  • Coronavirus RNA-Dependent RNA Polymerase
  • NSP12 protein, SARS-CoV-2
  • NSP7 protein, SARS-CoV-2
  • RNA-Dependent RNA Polymerase
  • Alanine