Free fatty acid binding pocket in the locked structure of SARS-CoV-2 spike protein

Science. 2020 Nov 6;370(6517):725-730. doi: 10.1126/science.abd3255. Epub 2020 Sep 21.

Abstract

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), represents a global crisis. Key to SARS-CoV-2 therapeutic development is unraveling the mechanisms that drive high infectivity, broad tissue tropism, and severe pathology. Our 2.85-angstrom cryo-electron microscopy structure of SARS-CoV-2 spike (S) glycoprotein reveals that the receptor binding domains tightly bind the essential free fatty acid linoleic acid (LA) in three composite binding pockets. A similar pocket also appears to be present in the highly pathogenic severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). LA binding stabilizes a locked S conformation, resulting in reduced angiotensin-converting enzyme 2 (ACE2) interaction in vitro. In human cells, LA supplementation synergizes with the COVID-19 drug remdesivir, suppressing SARS-CoV-2 replication. Our structure directly links LA and S, setting the stage for intervention strategies that target LA binding by SARS-CoV-2.

Publication types

  • Research Support, Non-U.S. Gov't
  • Video-Audio Media

MeSH terms

  • Amino Acid Sequence
  • Angiotensin-Converting Enzyme 2
  • Animals
  • Betacoronavirus
  • Binding Sites
  • Chlorocebus aethiops
  • Cryoelectron Microscopy
  • Humans
  • Linoleic Acid / metabolism*
  • Middle East Respiratory Syndrome Coronavirus
  • Models, Molecular
  • Peptidyl-Dipeptidase A / metabolism
  • Protein Interaction Domains and Motifs
  • Protein Structure, Tertiary
  • SARS Virus
  • SARS-CoV-2
  • Spike Glycoprotein, Coronavirus / chemistry*
  • Spike Glycoprotein, Coronavirus / ultrastructure
  • Vero Cells

Substances

  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2
  • Linoleic Acid
  • Peptidyl-Dipeptidase A
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2