The Free Fatty Acid-Binding Pocket is a Conserved Hallmark in Pathogenic β-Coronavirus Spike Proteins from SARS-CoV to Omicron

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Toelzer, Christine | Gupta, Kapil | Yadav, Sathish K.N. | Hodgson, Lorna | Williamson, Maia Kavanagh | Buzas, Dora | Borucu, Ufuk | Powers, Kyle | Stenner, Richard | Vasileiou, Kate | Garzoni, Frederic | Fitzgerald, Daniel | Payré, Christine | Lambeau, G. | Davidson, Andrew | Verkade, Paul | Frank, Martin | Berger, Imre | Schaffitzel, Christiane

Edité par CCSD -

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 Summary Free fatty acid-binding is conserved in pathogenic β-coronavirus S proteins and suppresses viral infection and replication.

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