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.
Highlights
SARS-CoV-2 has acquired functions that promote its harsh disease phenotype
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 attachment of SARS-CoV-2 to a host cell is initiated by the spike protein trimer (S), which decorates the outer surface of the virus, binding to its cognate receptor angiotensin-converting enzyme 2 (ACE2), with higher affinity than SARS-CoV [5,6,7]
Summary
SARS-CoV-2 has acquired functions that promote its harsh disease phenotype. SARS-CoV-2 causes severe inflammation and damage to endothelial cells in the heart, kidneys, liver and intestines, suggestive of a vascular infection rather than a purely respiratory disease [3, 4]. We superimposed our LA-bound structure on previous SARS-CoV-2 apo S structures in the closed conformation [7, 17] and identified a gating helix located directly at the entrance of the binding pocket (Fig. 3, A to C). In the apo SARS-CoV-2 S trimer [7, 17], a gap between adjacent RBDs places the hydrophilic anchor residues ~10 Å away from the position of the LA headgroup (Fig. 3C).
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