Conformational dynamics and allosteric modulation of the SARS-CoV-2 spike
- University of Massachusetts Medical School, United States
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects cells through binding to angiotensin-converting enzyme 2 (ACE2). This interaction is mediated by the receptor-binding domain (RBD) of the viral spike (S) glycoprotein. Structural and dynamic data have shown that S can adopt multiple conformations, which controls the exposure of the ACE2-binding site in the RBD. Here, using single-molecule Förster resonance energy transfer (smFRET) imaging we report the effects of ACE2 and antibody binding on the conformational dynamics of S from the Wuhan-1 strain and in the presence of the D614G mutation. We find that D614G modulates the energetics of the RBD position in a manner similar to ACE2 binding. We also find that antibodies that target diverse epitopes, including those distal to the RBD, stabilize the RBD in a position competent for ACE2 binding. Parallel solution-based binding experiments using fluorescence correlation spectroscopy (FCS) indicate antibody-mediated enhancement of ACE2 binding. These findings inform on novel strategies for therapeutic antibody cocktails.
Data availability
All data generated or analyzed during this study are included in the manuscript and supporting files.
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Author details
Funding
UMass Chan Medical School COVID-19 Pandemic Relief Fund
- James B Munro
National Institutes of Health (R37AI147868)
- Jeremy Luban
National Institutes of Health (R01AI148784)
- Jeremy Luban
- James B Munro
National Institutes of Health (K22CA241362)
- Kuang Shen
Evergrande COVID-19 Response Fund
- Jeremy Luban
Massachusetts Consortium on Pathogen Readiness
- Jeremy Luban
Worcester Foundation for Biomedical Research
- Kuang Shen
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2022, Diaz-Salinas 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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Conformational dynamics and allosteric modulation of the SARS-CoV-2 spike
eLife 11:e75433.
https://doi.org/10.7554/eLife.75433
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