Free fatty acid binding pocket in the locked structure of SARS-CoV-2 spike protein

Christine Toelzer; Kapil Gupta; Sathish K N Yadav; Ufuk Borucu; Andrew D Davidson; Maia Kavanagh Williamson; Deborah K Shoemark; Frederic Garzoni; Oskar Staufer; Rachel Milligan; Julien Capin; Adrian J Mulholland; Imre Berger; Christiane Schaffitzel

doi:10.1126/science.abd3255

Free fatty acid binding pocket in the locked structure of SARS-CoV-2 spike protein

Christine Toelzer, Kapil Gupta, Sathish K N Yadav, Ufuk Borucu, Andrew D Davidson, Maia Kavanagh Williamson, Deborah K Shoemark, Frederic Garzoni, Oskar Staufer, Rachel Milligan, Julien Capin, Adrian J Mulholland, Imre Berger, Christiane Schaffitzel

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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 2.85 Å cryo-EM structure of SARS-CoV-2 spike (S) glycoprotein reveals that the receptor binding domains (RBDs) tightly 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. LA binding stabilizes a locked S conformation giving rise to reduced ACE2 interaction in vitro. In human cells, LA supplementation synergizes with the COVID-19 drug remdesivir, suppressing SARS-CoV-2 replication. Our structure directly links LA and S, setting the stage for intervention strategies targeting LA binding by SARS-CoV-2.

Original language	English
Article number	eabd3255
Number of pages	12
Journal	Science
Volume	370
Issue number	6517
Early online date	21 Sept 2020
DOIs	https://doi.org/10.1126/science.abd3255
Publication status	Published - 6 Nov 2020

Research Groups and Themes

Bristol BioDesign Institute
Covid19
UNCOVER
BrisSynBio
Max Planck Bristol

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Toelzer, C., Gupta, K., Yadav, S. K. N., Borucu, U., Davidson, A. D., Kavanagh Williamson, M., Shoemark, D. K., Garzoni, F., Staufer, O., Milligan, R., Capin, J., Mulholland, A. J., Berger, I., & Schaffitzel, C. (2020). Free fatty acid binding pocket in the locked structure of SARS-CoV-2 spike protein. Science, 370(6517), Article eabd3255. https://doi.org/10.1126/science.abd3255

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title = "Free fatty acid binding pocket in the locked structure of SARS-CoV-2 spike protein",

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 2.85 {\AA} cryo-EM structure of SARS-CoV-2 spike (S) glycoprotein reveals that the receptor binding domains (RBDs) tightly 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. LA binding stabilizes a locked S conformation giving rise to reduced ACE2 interaction in vitro. In human cells, LA supplementation synergizes with the COVID-19 drug remdesivir, suppressing SARS-CoV-2 replication. Our structure directly links LA and S, setting the stage for intervention strategies targeting LA binding by SARS-CoV-2.",

author = "Christine Toelzer and Kapil Gupta and Yadav, {Sathish K N} and Ufuk Borucu and Davidson, {Andrew D} and {Kavanagh Williamson}, Maia and Shoemark, {Deborah K} and Frederic Garzoni and Oskar Staufer and Rachel Milligan and Julien Capin and Mulholland, {Adrian J} and Imre Berger and Christiane Schaffitzel",

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AU - Toelzer, Christine

AU - Gupta, Kapil

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AU - Davidson, Andrew D

AU - Kavanagh Williamson, Maia

AU - Shoemark, Deborah K

AU - Garzoni, Frederic

AU - Staufer, Oskar

AU - Milligan, Rachel

AU - Capin, Julien

AU - Mulholland, Adrian J

AU - Berger, Imre

AU - Schaffitzel, Christiane

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AB - 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 2.85 Å cryo-EM structure of SARS-CoV-2 spike (S) glycoprotein reveals that the receptor binding domains (RBDs) tightly 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. LA binding stabilizes a locked S conformation giving rise to reduced ACE2 interaction in vitro. In human cells, LA supplementation synergizes with the COVID-19 drug remdesivir, suppressing SARS-CoV-2 replication. Our structure directly links LA and S, setting the stage for intervention strategies targeting LA binding by SARS-CoV-2.

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DO - 10.1126/science.abd3255

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JO - Science

JF - Science

IS - 6517

M1 - eabd3255

ER -

Free fatty acid binding pocket in the locked structure of SARS-CoV-2 spike protein

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