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.
Article and author information
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.
Reviewing Editor
- Ruben L Gonzalez Jr, Columbia University, United States
Version history
- Preprint posted: November 1, 2021 (view preprint)
- Received: November 10, 2021
- Accepted: March 17, 2022
- Accepted Manuscript published: March 24, 2022 (version 1)
- Version of Record published: March 29, 2022 (version 2)
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.
Metrics
-
- 1,700
- views
-
- 346
- downloads
-
- 54
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Conformational dynamics and allosteric modulation of the SARS-CoV-2 spike
eLife 11:e75433.
https://doi.org/10.7554/eLife.75433
Further reading
-
- Epidemiology and Global Health
- Microbiology and Infectious Disease
Systematically tracking and analysing reproductive loss in livestock helps with efforts to safeguard the health and productivity of food animals by identifying causes and high-risk areas.
-
- Microbiology and Infectious Disease
Survival of Mycobacterium tuberculosis within the host macrophages requires the bacterial virulence regulator PhoP, but the underlying reason remains unknown. 3′,5′-Cyclic adenosine monophosphate (cAMP) is one of the most widely used second messengers, which impacts a wide range of cellular responses in microbial pathogens including M. tuberculosis. Herein, we hypothesized that intra-bacterial cAMP level could be controlled by PhoP since this major regulator plays a key role in bacterial responses against numerous stress conditions. A transcriptomic analysis reveals that PhoP functions as a repressor of cAMP-specific phosphodiesterase (PDE) Rv0805, which hydrolyzes cAMP. In keeping with these results, we find specific recruitment of the regulator within the promoter region of rv0805 PDE, and absence of phoP or ectopic expression of rv0805 independently accounts for elevated PDE synthesis, leading to the depletion of intra-bacterial cAMP level. Thus, genetic manipulation to inactivate PhoP-rv0805-cAMP pathway decreases cAMP level, stress tolerance, and intracellular survival of the bacillus.
