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SARS-CoV-2 S protein ACE2 interaction reveals novel allosteric targets (preprint)
biorxiv; 2020.
Preprint
in English
| bioRxiv | ID: ppzbmed-10.1101.2020.10.13.337212
ABSTRACT
The Spike (S) protein is the main handle for SARS-CoV-2 to enter host cells through surface ACE2 receptors. How ACE2 binding activates proteolysis of S protein is unknown. Here, we have mapped the SACE2 interface and uncovered long-range allosteric propagation of ACE2 binding to sites critical for viral host entry. Unexpectedly, ACE2 binding enhances dynamics at a distal S1/S2 cleavage site and flanking protease docking site ~27 [A] away while dampening dynamics of the stalk hinge (central helix and heptad repeat) regions ~ 130 [A] away. This highlights that the stalk and proteolysis sites of the S protein are dynamic hotspots in the pre-fusion state. Our findings provide a mechanistic basis for SACE2 complex formation, critical for proteolytic processing and viral-host membrane fusion and highlight protease docking sites flanking the S1/S2 cleavage site, fusion peptide and heptad repeat 1 (HR1) as allosterically exposed cryptic hotspots for potential therapeutic development.
Full text:
Available
Collection:
Preprints
Database:
bioRxiv
Language:
English
Year:
2020
Document Type:
Preprint
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