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

Christine Toelzer, Kapil Gupta, Sathish K N Yadav, Ufuk Borucu, Andrew D Davidson, Maia Kavanagh Williamson, Deborah K Shoemark, Frederic Garzoni, Oskar Staufer, Rachel Milligan, Julien Capin, Adrian J Mulholland, Imre Berger, Christiane Schaffitzel

Research output: Contribution to journalArticle (Academic Journal)peer-review

296 Citations (Scopus)
318 Downloads (Pure)

Abstract

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 driving high infectivity, broad tissue tropism and severe pathology. Our 2.85 Å cryo-EM structure of SARS-CoV-2 spike (S) glycoprotein reveals that the receptor binding domains (RBDs) tightly bind the essential free fatty acid (FFA) linoleic acid (LA) in three composite binding pockets. The pocket also appears to be present in the highly pathogenic coronaviruses SARS-CoV and MERS-CoV. LA binding stabilizes a locked S conformation giving rise to reduced 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 targeting LA binding by SARS-CoV-2.
Original languageEnglish
Article numbereabd3255
Number of pages12
JournalScience
Volume370
Issue number6517
Early online date21 Sept 2020
DOIs
Publication statusPublished - 6 Nov 2020

Research Groups and Themes

  • Bristol BioDesign Institute
  • Covid19
  • UNCOVER
  • BrisSynBio
  • Max Planck Bristol

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