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

View ORCID ProfileChristine Toelzer, View ORCID ProfileKapil Gupta, Sathish K.N. Yadav, View ORCID ProfileUfuk Borucu, Frederic Garzoni, View ORCID ProfileOskar Staufer, View ORCID ProfileJulien Capin, View ORCID ProfileJoachim Spatz, Daniel Fitzgerald, View ORCID ProfileImre Berger, View ORCID ProfileChristiane Schaffitzel
doi: https://doi.org/10.1101/2020.06.18.158584
Christine Toelzer
1School of Biochemistry, University of Bristol, 1 Tankard’s Close, Bristol BS8 1TD, UK
2Bristol Synthetic Biology Centre BrisSynBio, 24 Tyndall Ave, Bristol BS8 1TQ, UK
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Kapil Gupta
1School of Biochemistry, University of Bristol, 1 Tankard’s Close, Bristol BS8 1TD, UK
2Bristol Synthetic Biology Centre BrisSynBio, 24 Tyndall Ave, Bristol BS8 1TQ, UK
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Sathish K.N. Yadav
1School of Biochemistry, University of Bristol, 1 Tankard’s Close, Bristol BS8 1TD, UK
2Bristol Synthetic Biology Centre BrisSynBio, 24 Tyndall Ave, Bristol BS8 1TQ, UK
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Ufuk Borucu
1School of Biochemistry, University of Bristol, 1 Tankard’s Close, Bristol BS8 1TD, UK
2Bristol Synthetic Biology Centre BrisSynBio, 24 Tyndall Ave, Bristol BS8 1TQ, UK
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Frederic Garzoni
3Imophoron Ltd, St. Philips Central, Albert Rd, St. Philips, Bristol, BS2 0XJ, UK
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Oskar Staufer
4Department for Cellular Biophysics, Max Planck Institute for Medical Research, Jahnstraße 29, 69120 Heidelberg, Germany
5Institute for Physical Chemistry, Department for Biophysical Chemistry, University of Heidelberg, Im Neuenheimer Feld 253, 69120 Heidelberg, Germany
6Max Planck School Matter to Life, Jahnstraße 29, D-69120 Heidelberg, Germany
7Max Planck Bristol Centre for Minimal Biology, Cantock’s Close, Bristol BS8 1TS, UK
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Julien Capin
1School of Biochemistry, University of Bristol, 1 Tankard’s Close, Bristol BS8 1TD, UK
2Bristol Synthetic Biology Centre BrisSynBio, 24 Tyndall Ave, Bristol BS8 1TQ, UK
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Joachim Spatz
4Department for Cellular Biophysics, Max Planck Institute for Medical Research, Jahnstraße 29, 69120 Heidelberg, Germany
5Institute for Physical Chemistry, Department for Biophysical Chemistry, University of Heidelberg, Im Neuenheimer Feld 253, 69120 Heidelberg, Germany
6Max Planck School Matter to Life, Jahnstraße 29, D-69120 Heidelberg, Germany
7Max Planck Bristol Centre for Minimal Biology, Cantock’s Close, Bristol BS8 1TS, UK
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Daniel Fitzgerald
8Geneva Biotech Sàrl, Avenue de la Roseraie 64, 1205, Geneva, Switzerland
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Imre Berger
1School of Biochemistry, University of Bristol, 1 Tankard’s Close, Bristol BS8 1TD, UK
2Bristol Synthetic Biology Centre BrisSynBio, 24 Tyndall Ave, Bristol BS8 1TQ, UK
7Max Planck Bristol Centre for Minimal Biology, Cantock’s Close, Bristol BS8 1TS, UK
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  • For correspondence: cb14941@bristol.ac.uk imre.berger@bristol.ac.uk
Christiane Schaffitzel
1School of Biochemistry, University of Bristol, 1 Tankard’s Close, Bristol BS8 1TD, UK
2Bristol Synthetic Biology Centre BrisSynBio, 24 Tyndall Ave, Bristol BS8 1TQ, UK
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  • For correspondence: cb14941@bristol.ac.uk imre.berger@bristol.ac.uk
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Abstract

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.

One Sentence Summary A direct structural link between SARS-CoV-2 spike and linoleic acid, a key molecule in inflammation, immune modulation and membrane fluidity.

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.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted June 18, 2020.
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Unexpected free fatty acid binding pocket in the cryo-EM structure of SARS-CoV-2 spike protein
Christine Toelzer, Kapil Gupta, Sathish K.N. Yadav, Ufuk Borucu, Frederic Garzoni, Oskar Staufer, Julien Capin, Joachim Spatz, Daniel Fitzgerald, Imre Berger, Christiane Schaffitzel
bioRxiv 2020.06.18.158584; doi: https://doi.org/10.1101/2020.06.18.158584
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Unexpected free fatty acid binding pocket in the cryo-EM structure of SARS-CoV-2 spike protein
Christine Toelzer, Kapil Gupta, Sathish K.N. Yadav, Ufuk Borucu, Frederic Garzoni, Oskar Staufer, Julien Capin, Joachim Spatz, Daniel Fitzgerald, Imre Berger, Christiane Schaffitzel
bioRxiv 2020.06.18.158584; doi: https://doi.org/10.1101/2020.06.18.158584

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