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.

中文翻译：

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膜中 SARS-CoV-2 尖峰重折叠的结构和抑制


严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 刺突蛋白与受体血管紧张素转换酶 2 (ACE2) 结合，并通过其 S2 结构域的重折叠驱动病毒与宿主膜融合。尽管 S1 结构域包含高序列变异性，但 S2 结构域是保守的，是一个有前途的泛 β 冠状病毒疫苗靶标。我们应用冷冻电子断层扫描来捕获 S2 重折叠的中间体并了解 S2 茎螺旋抗体的抑制作用。亚断层图平均显示 ACE2 二聚体在转变为 S2 中间体之前交联尖峰，这些中间体在重折叠的各个阶段被捕获。靶向 S2 茎螺旋的泛 β 冠状病毒中和抗体与刺突前发夹中间体结合并抑制其重折叠。结合分子动力学模拟，这些结构阐明了 SARS-CoV-2 进入的过程，并揭示了泛 β 冠状病毒 S2 靶向抗体如何通过阻止前发夹中间体来中和感染性。