SARS-CoV-2 S protein:ACE2 interaction reveals novel allosteric targets
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Open Access
- 8 February 2021
- journal article
- research article
- Published by eLife Sciences Publications, Ltd in eLife
Abstract
The Spike (S) protein is the main handle for SARS-CoV-2 to enter host cells via surface ACE2 receptors. How ACE2 binding activates proteolysis of S protein is unknown. Here, using amide hydrogen-deuterium exchange mass spectrometry and molecular dynamics simulations, we have mapped the S:ACE2 interaction interface and uncovered long-range allosteric propagation of ACE2 binding to sites necessary for host-mediated proteolysis of S protein, critical for viral host entry. Unexpectedly, ACE2 binding enhances dynamics at a distal S1/S2 cleavage site and flanking protease docking site ~27 Å away while dampening dynamics of the stalk hinge (central helix and heptad repeat) regions ~130 Å 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 dynamics map of the S:ACE2 interface in solution and also offer mechanistic insights into how ACE2 binding is allosterically coupled to distal proteolytic processing sites and viral-host membrane fusion. Our findings highlight protease docking sites flanking the S1/S2 cleavage site, fusion peptide and heptad repeat 1 (HR1) as alternate allosteric hotspot targets for potential therapeutic development.Funding Information
- National Medical Research Council (WBS#R-571-000-081-213 Establishment of assays for drug screening and virus characterization of the newly emerged novel coronavirus (2019-nCoV) which is also known as the Wuhan coronavirus)
- A*STAR Bioinformatics Institute
- National University of Singapore
- Ministry of Education - Singapore (MOE2017-T2-A40-112)
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