Structure of the RNA-dependent RNA Polymerase From COVID-19 Virus

Science. 2020 May 15;368(6492):779-782. doi: 10.1126/science.abb7498. Epub 2020 Apr 10.

Abstract

A novel coronavirus [severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2)] outbreak has caused a global coronavirus disease 2019 (COVID-19) pandemic, resulting in tens of thousands of infections and thousands of deaths worldwide. The RNA-dependent RNA polymerase [(RdRp), also named nsp12] is the central component of coronaviral replication and transcription machinery, and it appears to be a primary target for the antiviral drug remdesivir. We report the cryo-electron microscopy structure of COVID-19 virus full-length nsp12 in complex with cofactors nsp7 and nsp8 at 2.9-angstrom resolution. In addition to the conserved architecture of the polymerase core of the viral polymerase family, nsp12 possesses a newly identified β-hairpin domain at its N terminus. A comparative analysis model shows how remdesivir binds to this polymerase. The structure provides a basis for the design of new antiviral therapeutics that target viral RdRp.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Monophosphate / analogs & derivatives
  • Adenosine Monophosphate / metabolism
  • Adenosine Monophosphate / pharmacology
  • Alanine / analogs & derivatives
  • Alanine / metabolism
  • Alanine / pharmacology
  • Antiviral Agents / metabolism
  • Antiviral Agents / pharmacology
  • Betacoronavirus / enzymology*
  • Catalytic Domain
  • Cryoelectron Microscopy
  • Drug Design
  • Models, Molecular
  • Multiprotein Complexes / chemistry
  • Multiprotein Complexes / metabolism
  • Multiprotein Complexes / ultrastructure
  • Protein Conformation, beta-Strand
  • Protein Domains
  • RNA Replicase / antagonists & inhibitors
  • RNA Replicase / chemistry*
  • RNA Replicase / metabolism
  • RNA Replicase / ultrastructure*
  • Viral Nonstructural Proteins / antagonists & inhibitors
  • Viral Nonstructural Proteins / chemistry*
  • Viral Nonstructural Proteins / metabolism
  • Viral Nonstructural Proteins / ultrastructure*

Substances

  • Antiviral Agents
  • Multiprotein Complexes
  • NSP7 protein, SARS-CoV-2
  • NSP8 protein, SARS-CoV-2
  • Viral Nonstructural Proteins
  • remdesivir
  • Adenosine Monophosphate
  • RNA Replicase
  • RNA-dependent RNA polymerase, coronavirus
  • Alanine

Supplementary concepts

  • severe acute respiratory syndrome coronavirus 2