학술논문
Free fatty acid binding pocket in the locked structure of SARS-CoV-2 spike protein.
Document Type
Article
Author
Toelzer, Christine; Gupta, Kapil; Yadav, Sathish K. N.; Borucu, Ufuk; Davidson, Andrew D.; Williamson, Maia Kavanagh; Shoemark, Deborah K.; Garzoni, Frederic; Staufer, Oskar; Milligan, Rachel; Capin, Julien; Mulholland, Adrian J.; Spatz, Joachim; Fitzgerald, Daniel; Berger, Imre; Schaffitzel, Christiane
Source
Subject
*COVID-19
*FATTY acids
*PROTEINS
*BINDING site assay
*GLYCOPROTEINS
*
*
*
*
Language
ISSN
0036-8075
Abstract
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. [ABSTRACT FROM AUTHOR]