Structure and inhibition of SARS-CoV-2 spike refolding in membranes.
Science
; 385(6710): 757-765, 2024 Aug 16.
Article
in En
| MEDLINE
| ID: mdl-39146425
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Cryoelectron Microscopy
/
Antibodies, Neutralizing
/
Molecular Dynamics Simulation
/
Spike Glycoprotein, Coronavirus
/
Protein Domains
/
Angiotensin-Converting Enzyme 2
/
SARS-CoV-2
/
Antibodies, Viral
Limits:
Humans
Language:
En
Journal:
Science
Year:
2024
Type:
Article
Affiliation country:
United States