Structure and inhibition of SARS-CoV-2 spike refolding in membranes.
Michael W GrunstZhuan QinEsteban Dodero-RojasShilei DingJérémie PrévostYaozong ChenYanping HuMarzena E PazgierShenping WuXuping XieAndrés FinziJosé Nelson OnuchicPaul Charles WhitfordWalther MothesWenwei LiPublished in: Science (New York, N.Y.) (2024)
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.
Keyphrases
- sars cov
- respiratory syndrome coronavirus
- angiotensin converting enzyme
- molecular dynamics simulations
- angiotensin ii
- high resolution
- coronavirus disease
- cancer therapy
- single cell
- electron microscopy
- dna binding
- molecular docking
- transcription factor
- binding protein
- amino acid
- genome wide
- gene expression
- zika virus