Back to Search
Start Over
Structure and inhibition of SARS-CoV-2 spike refolding in membranes.
- Source :
-
Science (New York, N.Y.) [Science] 2024 Aug 16; Vol. 385 (6710), pp. 757-765. Date of Electronic Publication: 2024 Aug 15. - Publication Year :
- 2024
-
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.
- Subjects :
- Humans
Virus Internalization
Protein Refolding
Electron Microscope Tomography
Protein Multimerization
Betacoronavirus immunology
Betacoronavirus chemistry
Cell Membrane metabolism
COVID-19 virology
COVID-19 immunology
Peptidyl-Dipeptidase A chemistry
Peptidyl-Dipeptidase A metabolism
Spike Glycoprotein, Coronavirus chemistry
Spike Glycoprotein, Coronavirus metabolism
Spike Glycoprotein, Coronavirus immunology
Spike Glycoprotein, Coronavirus genetics
SARS-CoV-2 immunology
SARS-CoV-2 genetics
Angiotensin-Converting Enzyme 2 metabolism
Angiotensin-Converting Enzyme 2 chemistry
Molecular Dynamics Simulation
Antibodies, Neutralizing immunology
Antibodies, Neutralizing chemistry
Cryoelectron Microscopy
Antibodies, Viral immunology
Antibodies, Viral chemistry
Protein Domains
Subjects
Details
- Language :
- English
- ISSN :
- 1095-9203
- Volume :
- 385
- Issue :
- 6710
- Database :
- MEDLINE
- Journal :
- Science (New York, N.Y.)
- Publication Type :
- Academic Journal
- Accession number :
- 39146425
- Full Text :
- https://doi.org/10.1126/science.adn5658