Structure and inhibition of SARS-CoV-2 spike refolding in membranes-Reference-Cited by-同舟云学术

Structure and inhibition of SARS-CoV-2 spike refolding in membranes

Published:2024-08-16 Issue:6710 Volume:385 Page:757-765
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Grunst Michael W.¹^ORCID,Qin Zhuan¹^ORCID,Dodero-Rojas Esteban²^ORCID,Ding Shilei³,Prévost Jérémie³⁴^ORCID,Chen Yaozong⁵,Hu Yanping⁶,Pazgier Marzena⁵^ORCID,Wu Shenping⁷,Xie Xuping⁶^ORCID,Finzi Andrés³⁴^ORCID,Onuchic José N.²⁸⁹¹⁰^ORCID,Whitford Paul C.¹¹¹²^ORCID,Mothes Walther¹^ORCID,Li Wenwei¹^ORCID

Affiliation:

1. Department of Microbial Pathogenesis, Yale University, New Haven, CT, USA.

2. Center for Theoretical Biological Physics, Rice University, Houston, TX, USA.

3. Centre de Recherche du CHUM, Montréal, QC H2X 0A9, Canada.

4. Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montréal, QC H3T 1J4, Canada.

5. Infectious Disease Division, Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814-4712, USA.

6. Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA.

7. Department of Pharmacology, Yale University, West Haven, CT 06516, USA.

8. Department of Physics and Astronomy, Rice University, Houston, TX, USA.

9. Department of Chemistry, Rice University, Houston, TX, USA.

10. Department of Biosciences, Rice University, Houston, TX, USA.

11. Center for Theoretical Biological Physics, Northeastern University, Boston, MA, USA.

12. Department of Physics, Northeastern University, Boston, MA, USA.

Abstract

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.

Publisher

American Association for the Advancement of Science (AAAS)

Link

https://www.science.org/doi/pdf/10.1126/science.adn5658

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