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Sci Adv
. 2022 Nov 25;8(47):eadc9179.
doi: 10.1126/sciadv.adc9179. Epub 2022 Nov 23.
The free fatty acid-binding pocket is a conserved hallmark in pathogenic β-coronavirus spike proteins from SARS-CoV to Omicron
Christine Toelzer 1 2 , Kapil Gupta 1 2 3 , Sathish K N Yadav 1 2 , Lorna Hodgson 1 2 , Maia Kavanagh Williamson 4 , Dora Buzas 1 2 5 , Ufuk Borucu 1 2 , Kyle Powers 1 2 , Richard Stenner 1 2 , Kate Vasileiou 1 2 , Frederic Garzoni 3 , Daniel Fitzgerald 6 , Christine Payré 7 , Gunjan Gautam 1 2 , Gérard Lambeau 7 , Andrew D Davidson 4 , Paul Verkade 1 2 , Martin Frank 8 , Imre Berger 1 2 5 6 9 , Christiane Schaffitzel 1 2 6
Affiliations
- PMID: 36417532
- DOI: 10.1126/sciadv.adc9179
Abstract
As coronavirus disease 2019 (COVID-19) persists, severe acute 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 devoid of LA. 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, setting the stage for FFA-based antiviral strategies to overcome COVID-19.