Sars-cov-2 s protein:Ace2 interaction reveals novel allosteric targets

Palur V. Raghuvamsi, Nikhil K. Tulsian, Firdaus Samsudin, Xinlei Qian, Kiren Purushotorman, Gu Yue, Mary M. Kozma, Wong Y. Hwa, Julien Lescar, Peter J. Bond, Paul A. Macary, Ganesh S. Anand

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article numbere63646
Pages (from-to)1-47
Number of pages47
JournaleLife
Volume10
DOIs
StatePublished - Feb 2021

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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