1. The free fatty acid–binding pocket is a conserved hallmark in pathogenic β-coronavirus spike proteins from SARS-CoV to Omicron
- Author
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Christine Toelzer, Kapil Gupta, Sathish K. N. Yadav, Lorna Hodgson, Maia Kavanagh Williamson, Dora Buzas, Ufuk Borucu, Kyle Powers, Richard Stenner, Kate Vasileiou, Frederic Garzoni, Daniel Fitzgerald, Christine Payré, Gunjan Gautam, Gérard Lambeau, Andrew D. Davidson, Paul Verkade, Martin Frank, Imre Berger, and Christiane Schaffitzel
- Subjects
Multidisciplinary ,SARS-CoV-2 ,Max Planck Bristol ,Spike Glycoprotein, Coronavirus ,Bristol BioDesign Institute ,Humans ,COVID-19 ,Fatty Acids, Nonesterified - Abstract
As COVID-19 persists, severe acquired respiratory syndrome coronavirus-2 (SARS-CoV-2) Variants of Concern (VOCs) emerge, accumulating spike (S) glycoprotein mutations. S receptor-binding domain (RBD) comprises a free fatty acid (FFA)-binding pocket. FFA-binding stabilizes a locked S conformation, interfering with virus infectivity. We provide evidence that the pocket is conserved in pathogenic β-coronaviruses (β-CoVs) infecting humans. SARS-CoV, MERS-CoV, SARS-CoV-2 and VOCs bind the essential FFA linoleic acid (LA), while binding is abolished by one mutation in common cold-causing HCoV-HKU1. In the SARS-CoV S structure, LA stabilizes the locked conformation while the open, infectious conformation is LA-free. Electron tomography of SARS-CoV-2 infected cells reveals that LA-treatment inhibits viral replication, resulting in fewer, deformed virions. Our results establish FFA-binding as a hallmark of pathogenic β-CoV infection and replication, highlighting potential antiviral strategies.One-Sentence SummaryFree fatty acid-binding is conserved in pathogenic β-coronavirus S proteins and suppresses viral infection and replication.
- Published
- 2022