1. Biochemistry and Chemical Biology
  2. Structural Biology and Molecular Biophysics
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SARS-CoV-2 S protein:ACE2 interaction reveals novel allosteric targets

  1. Palur V Raghuvamsi
  2. Nikhil Kumar Tulsian
  3. Firdaus Samsudin
  4. Xinlei Qian
  5. Kiren Purushotorman
  6. Gu Yue
  7. Mary M Kozma
  8. Wong Yee Hwa
  9. Julien Lescar
  10. Peter J Bond  Is a corresponding author
  11. Paul Anthony MacAry  Is a corresponding author
  12. Ganesh Srinivasan Anand  Is a corresponding author
  1. National University of Singapore, Singapore
  2. A*STAR, Singapore
  3. National Technological University, Singapore
Research Article
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Cite this article as: eLife 2021;10:e63646 doi: 10.7554/eLife.63646

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.

Article and author information

Author details

  1. Palur V Raghuvamsi

    Biological Sciences, National University of Singapore, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0897-6935
  2. Nikhil Kumar Tulsian

    Biological Sciences, National University of Singapore, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  3. Firdaus Samsudin

    Bioinformatics Institute, A*STAR, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  4. Xinlei Qian

    Life Sciences Institute, National University of Singapore, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  5. Kiren Purushotorman

    Microbiology and Immunology, National University of Singapore, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  6. Gu Yue

    Microbiology and Immunology, National University of Singapore, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  7. Mary M Kozma

    Life Sciences Institute, National University of Singapore, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  8. Wong Yee Hwa

    School of Biological Sciences, National Technological University, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  9. Julien Lescar

    School of Biological Sciences, National Technological University, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  10. Peter J Bond

    Microbiology and Immunology, National University of Singapore, Singapore, Singapore
    For correspondence
    peterjb@bii.a-star.edu.sg
    Competing interests
    The authors declare that no competing interests exist.
  11. Paul Anthony MacAry

    Microbiology and Immunology, National University of Singapore, Singapore, Singapore
    For correspondence
    micpam@nus.edu.sg
    Competing interests
    The authors declare that no competing interests exist.
  12. Ganesh Srinivasan Anand

    Biological Sciences, National University of Singapore, Singapore, Singapore
    For correspondence
    gsa5089@psu.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8995-3067

Funding

Ministry of Education - Singapore (Research Fellowship)

  • Ganesh Srinivasan Anand

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Donald Hamelberg, Georgia State University, United States

Publication history

  1. Received: October 1, 2020
  2. Accepted: February 5, 2021
  3. Accepted Manuscript published: February 8, 2021 (version 1)

Copyright

© 2021, Raghuvamsi et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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