SARS-CoV-2 is thought to have emerged from bats, possibly via a secondary host. Here, we investigate the relationship of spike (S) glycoprotein from SARS-CoV-2 with the S protein of a closely related bat virus, RaTG13. We determined cryo-EM structures for RaTG13 S and for both furin-cleaved and uncleaved SARS-CoV-2 S; we compared these with recently reported structures for uncleaved SARS-CoV-2 S. We also biochemically characterized their relative stabilities and affinities for the SARS-CoV-2 receptor ACE2. Although the overall structures of human and bat virus S proteins are similar, there are key differences in their properties, including a more stable precleavage form of human S and about 1,000-fold tighter binding of SARS-CoV-2 to human receptor. These observations suggest that cleavage at the furin-cleavage site decreases the overall stability of SARS-CoV-2 S and facilitates the adoption of the open conformation that is required for S to bind to the ACE2 receptor.

SARS-CoV-2被认为是从蝙蝠中产生的，可能是通过第二宿主产生的。在这里，我们研究了 SARS-CoV-2 的刺突 (S) 糖蛋白与密切相关的蝙蝠病毒 RaTG13 的 S 蛋白的关系。我们确定了 RaTG13 S 以及弗林蛋白酶切割和未切割的 SARS-CoV-2 S 的冷冻电镜结构；我们将它们与最近报道的未切割的 SARS-CoV-2 S 的结构进行了比较。我们还通过生化方法表征了它们对 SARS-CoV-2 受体 ACE2 的相对稳定性和亲和力。尽管人类和蝙蝠病毒 S 蛋白的整体结构相似，但它们的特性存在关键差异，包括人类 S 的预切割形式更稳定，以及 SARS-CoV-2 与人类受体的结合紧密约 1,000 倍。这些观察结果表明，弗林蛋白酶切割位点的切割降低了 SARS-CoV-2 S 的整体稳定性，并促进采用 S 与 ACE2 受体结合所需的开放构象。