Structural Biology of Disease Processes Laboratory, Francis Crick Institute, London, UK.
Precision Medicine Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China.
Nat Struct Mol Biol. 2020 Aug;27(8):763-767. doi: 10.1038/s41594-020-0468-7. Epub 2020 Jul 9.
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 被认为是源自蝙蝠，可能通过中间宿主传播。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 蛋白之间的关系。我们确定了 RaTG13 S 的冷冻电镜结构，以及两种弗林蛋白酶切割和未切割的 SARS-CoV-2 S 的结构；我们将这些结构与最近报道的未切割 SARS-CoV-2 S 的结构进行了比较。我们还对它们的相对稳定性和与 SARS-CoV-2 受体 ACE2 的亲和力进行了生化表征。尽管人类和蝙蝠病毒 S 蛋白的整体结构相似，但它们在性质上存在关键差异，包括人类 S 蛋白更稳定的前切割形式，以及 SARS-CoV-2 与人类受体结合的亲和力约高 1000 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，并促进了其开放构象的形成，这是 S 蛋白与 ACE2 受体结合所必需的。
