Structure and inhibition of SARS-CoV-2 spike refolding in membranes

• 成果类型: Article
• 署名作者: Grunst, Michael W.; Qin, Zhuan; Dodero-Rojas, Esteban; Ding, Shilei; Prevost, Jeremie; Chen, Yaozong; Hu, Yanping; Pazgier, Marzena; Wu, Shenping; Xie, Xuping; Finzi, Andres; Onuchic, Jose N.; Whitford, Paul C.; Mothes, Walther; Li, Wenwei
• 署名单位: Yale University; Rice University; Universite de Montreal; Universite de Montreal; Uniformed Services University of the Health Sciences - USA; University of Texas System; University of Texas Medical Branch Galveston; Yale University; Rice University; Rice University; Rice University; Northeastern University; Northeastern University
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8959
• DOI: 10.1126/science.adn5658
• 发表日期: 2024-08-16
• 页码: 757-765
• 关键词: antibodies protect; crystal-structure; cryo-em; DYNAMICS; reconstruction; mechanics; reveals

摘要

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.