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

Christine Toelzer | Zendy; Kapil Gupta | Zendy; Sathish K.N. Yadav | Zendy; Ufuk Borucu | Zendy; Andrew D. Davidson | Zendy; Maia Kavanagh Williamson | Zendy; Deborah K. Shoemark | Zendy; Frédéric Garzoni | Zendy; Oskar Staufer | Zendy; Rachel Milligan | Zendy; Julien Capin | Zendy; Adrian J. Mulholland | Zendy; Joachim P. Spatz | Zendy; Daniel J. Fitzgerald | Zendy; Imre Berger | Zendy; Christiane Schaffitzel | Zendy

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

Author(s) -

Christine Toelzer,

Kapil Gupta,

Sathish K.N. Yadav,

Ufuk Borucu,

Andrew D. Davidson,

Maia Kavanagh Williamson,

Deborah K. Shoemark,

Frédéric Garzoni,

Oskar Staufer,

Rachel Milligan,

Julien Capin,

Adrian J. Mulholland,

Joachim P. Spatz,

Daniel J. Fitzgerald,

Imre Berger,

Christiane Schaffitzel

Publication year - 2020

Publication title -

science

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 12.556

H-Index - 1186

eISSN - 1095-9203

pISSN - 0036-8075

DOI - 10.1126/science.abd3255

Subject(s) - trimer , spike protein , coronavirus , covid-19 , binding domain , protein structure , plasma protein binding , receptor , chemistry , viral protein , binding site , biochemistry , biology , virology , virus , medicine , dimer , disease , organic chemistry , pathology , infectious disease (medical specialty)

Coronavirus disease 2019 (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 that drive high infectivity, broad tissue tropism, and severe pathology. Our 2.85-angstrom cryo-electron microscopy structure of SARS-CoV-2 spike (S) glycoprotein reveals that the receptor binding domains tightly bind the essential free fatty acid linoleic acid (LA) in three composite binding pockets. A similar pocket also appears to be present in the highly pathogenic severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). LA binding stabilizes a locked S conformation, resulting in reduced angiotensin-converting enzyme 2 (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 that target LA binding by SARS-CoV-2.

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