Source Data: 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 anti-S2 stem-helix antibodies. 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.