tetano
Editor, Senior Moderator
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[SUP] 1 2 [/SUP], Kapil Gupta[SUP] 1 2 3 [/SUP], Sathish K N Yadav[SUP] 1 2 [/SUP], Lorna Hodgson[SUP] 1 2 [/SUP], Maia Kavanagh Williamson[SUP] 4 [/SUP], Dora Buzas[SUP] 1 2 5 [/SUP], Ufuk Borucu[SUP] 1 2 [/SUP], Kyle Powers[SUP] 1 2 [/SUP], Richard Stenner[SUP] 1 2 [/SUP], Kate Vasileiou[SUP] 1 2 [/SUP], Frederic Garzoni[SUP] 3 [/SUP], Daniel Fitzgerald[SUP] 6 [/SUP], Christine Payré[SUP] 7 [/SUP], Gunjan Gautam[SUP] 1 2 [/SUP], Gérard Lambeau[SUP] 7 [/SUP], Andrew D Davidson[SUP] 4 [/SUP], Paul Verkade[SUP] 1 2 [/SUP], Martin Frank[SUP] 8 [/SUP], Imre Berger[SUP] 1 2 5 6 9 [/SUP], Christiane Schaffitzel[SUP] 1 2 6 [/SUP]
Affiliations
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.
. 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[SUP] 1 2 [/SUP], Kapil Gupta[SUP] 1 2 3 [/SUP], Sathish K N Yadav[SUP] 1 2 [/SUP], Lorna Hodgson[SUP] 1 2 [/SUP], Maia Kavanagh Williamson[SUP] 4 [/SUP], Dora Buzas[SUP] 1 2 5 [/SUP], Ufuk Borucu[SUP] 1 2 [/SUP], Kyle Powers[SUP] 1 2 [/SUP], Richard Stenner[SUP] 1 2 [/SUP], Kate Vasileiou[SUP] 1 2 [/SUP], Frederic Garzoni[SUP] 3 [/SUP], Daniel Fitzgerald[SUP] 6 [/SUP], Christine Payré[SUP] 7 [/SUP], Gunjan Gautam[SUP] 1 2 [/SUP], Gérard Lambeau[SUP] 7 [/SUP], Andrew D Davidson[SUP] 4 [/SUP], Paul Verkade[SUP] 1 2 [/SUP], Martin Frank[SUP] 8 [/SUP], Imre Berger[SUP] 1 2 5 6 9 [/SUP], Christiane Schaffitzel[SUP] 1 2 6 [/SUP]
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.