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Unexpected free fatty acid binding pocket in the cryo-EM structure of SARS-CoV-2 spike protein

By Christine Toelzer, Kapil Gupta, Sathish KN Yadav, Ufuk Borucu, Frederic Garzoni, Oskar Staufer, Julien Capin, Joachim Spatz, Daniel Fitzgerald, Imre Berger, Christiane Schaffitzel

Posted 18 Jun 2020
bioRxiv DOI: 10.1101/2020.06.18.158584

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 cryo-EM structure of SARS-CoV-2 spike (S) glycoprotein reveals that the receptor binding domains (RBDs) tightly and specifically 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. Lipid metabolome remodeling is a key feature of coronavirus infection, with LA at its core. LA metabolic pathways are central to inflammation, immune modulation and membrane fluidity. Our structure directly links LA and S, setting the stage for interventions targeting LA binding and metabolic remodeling by SARS-CoV-2. ### Competing Interest Statement I.B. and D.F. report shareholding in Geneva Biotech SARL unrelated to this Correspondence. I.B and F.G. report shareholding in Imophoron Ltd. unrelated to this Correspondence. A patent application describing drug discovery methods and therapeutic interventions based on the present observations has been filed.

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