Structure and inhibition of SARS-CoV-2 spike refolding in membranes
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein binds the receptor angiotensin converting enzyme 2 (ACE2) and drives virus-host membrane fusion through refolding of its S2 domain. Whereas the S1 domain contains high sequence variability, the S2 domain is conserved and is a promising pan-betacoronavirus vaccine target. We applied cryo-electron tomography to capture intermediates of S2 refolding and understand inhibition by antibodies to the S2 stem-helix. Subtomogram averaging revealed ACE2 dimers cross-linking spikes before transitioning into S2 intermediates, which were captured at various stages of refolding. Pan-betacoronavirus neutralizing antibodies targeting the S2 stem-helix bound to and inhibited refolding of spike prehairpin intermediates. Combined with molecular dynamics simulations, these structures elucidate the process of SARS-CoV-2 entry and reveal how pan-betacoronavirus S2-targeting antibodies neutralize infectivity by arresting prehairpin intermediates.
Authors
- Michael W. Grunst (ORCID: https://orcid.org/0000-0002-8575-8026)
- Jérémie Prévost (ORCID: https://orcid.org/0000-0002-5260-5154)
- Esteban Dodero‐Rojas (ORCID: https://orcid.org/0000-0001-9054-9555)
- Xuping Xie (ORCID: https://orcid.org/0000-0003-0918-016X)
- Walther Mothes
- Yanping Hu (ORCID: https://orcid.org/0009-0006-8820-7437)
- José N. Onuchic (ORCID: https://orcid.org/0000-0002-9448-0388)
- Marzena Pazgier (ORCID: https://orcid.org/0000-0003-0594-5057)
- Zhuan Qin (ORCID: https://orcid.org/0000-0001-9112-7645)
- Paul C. Whitford (ORCID: https://orcid.org/0000-0001-7104-2265)
- Andrés Finzi (ORCID: https://orcid.org/0000-0002-4992-5288)
- Shenping Wu (ORCID: https://orcid.org/0000-0002-4295-4318)
- Yaozong Chen (ORCID: https://orcid.org/0000-0001-5380-2339)
- Wenwei Li (ORCID: https://orcid.org/0000-0003-3008-6901)
- Shilei Ding (ORCID: https://orcid.org/0000-0003-1895-5131)
Institutions
- Northeastern University (US)
- Uniformed Services University of the Health Sciences (US)
- Yale University (US)
- University of New Haven (US)
- Centre Hospitalier de l’Université de Montréal (CA)
- Center for Theoretical Biological Physics (US)
- The University of Texas Medical Branch at Galveston (US)
- Université de Montréal (CA)
- Rice University (US)
Publication Details
- Journal
- Science
- Published
- 2024-08-15
- DOI
- https://doi.org/10.1126/science.adn5658
- Citations
- 47
- Primary Topic
- SARS-CoV-2 and COVID-19 Research
- Type
- article
- Field-Weighted Citation Impact
- 18.28
Funders
- National Science Foundation
- U.S. Department of Defense
- Yale University
- National Institutes of Health
- Uniformed Services University of the Health Sciences
- Canadian Institutes of Health Research