tetano
Editor, Senior Moderator
Science
. 2024 Aug 16;385(6710):757-765.
doi: 10.1126/science.adn5658. Epub 2024 Aug 15. Structure and inhibition of SARS-CoV-2 spike refolding in membranes
Michael W Grunst[SUP] 1 [/SUP], Zhuan Qin[SUP] #[/SUP][SUP] 1 [/SUP], Esteban Dodero-Rojas[SUP] #[/SUP][SUP] 2 [/SUP], Shilei Ding[SUP] 3 [/SUP], Jérémie Prévost[SUP] 3 4 [/SUP], Yaozong Chen[SUP] 5 [/SUP], Yanping Hu[SUP] 6 [/SUP], Marzena Pazgier[SUP] 5 [/SUP], Shenping Wu[SUP] 7 [/SUP], Xuping Xie[SUP] 6 [/SUP], Andrés Finzi[SUP] 3 4 [/SUP], José N Onuchic[SUP] 2 8 9 10 [/SUP], Paul C Whitford[SUP] 11 12 [/SUP], Walther Mothes[SUP] 1 [/SUP], Wenwei Li[SUP] 1 [/SUP]
Affiliations
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.
. 2024 Aug 16;385(6710):757-765.
doi: 10.1126/science.adn5658. Epub 2024 Aug 15. Structure and inhibition of SARS-CoV-2 spike refolding in membranes
Michael W Grunst[SUP] 1 [/SUP], Zhuan Qin[SUP] #[/SUP][SUP] 1 [/SUP], Esteban Dodero-Rojas[SUP] #[/SUP][SUP] 2 [/SUP], Shilei Ding[SUP] 3 [/SUP], Jérémie Prévost[SUP] 3 4 [/SUP], Yaozong Chen[SUP] 5 [/SUP], Yanping Hu[SUP] 6 [/SUP], Marzena Pazgier[SUP] 5 [/SUP], Shenping Wu[SUP] 7 [/SUP], Xuping Xie[SUP] 6 [/SUP], Andrés Finzi[SUP] 3 4 [/SUP], José N Onuchic[SUP] 2 8 9 10 [/SUP], Paul C Whitford[SUP] 11 12 [/SUP], Walther Mothes[SUP] 1 [/SUP], Wenwei Li[SUP] 1 [/SUP]
Affiliations
- PMID: 39146425
- DOI: 10.1126/science.adn5658
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.