State Key Laboratory of Molecular Biology, National Center for Protein Science Shanghai, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China.
University of Chinese Academy of Sciences, Beijing 100049, China.
Sci Adv. 2021 Jan 1;7(1). doi: 10.1126/sciadv.abe5575. Print 2021 Jan.
The recent outbreaks of SARS-CoV-2 pose a global health emergency. The SARS-CoV-2 trimeric spike (S) glycoprotein interacts with the human ACE2 receptor to mediate viral entry into host cells. We report the cryo-EM structures of a tightly closed SARS-CoV-2 S trimer with packed fusion peptide and an ACE2-bound S trimer at 2.7- and 3.8-Å resolution, respectively. Accompanying ACE2 binding to the up receptor-binding domain (RBD), the associated ACE2-RBD exhibits continuous swing motions. Notably, the SARS-CoV-2 S trimer appears much more sensitive to the ACE2 receptor than the SARS-CoV S trimer regarding receptor-triggered transformation from the closed prefusion state to the fusion-prone open state, potentially contributing to the superior infectivity of SARS-CoV-2. We defined the RBD T470-T478 loop and Y505 as viral determinants for specific recognition of SARS-CoV-2 RBD by ACE2. Our findings depict the mechanism of ACE2-induced S trimer conformational transitions from the ground prefusion state toward the postfusion state, facilitating development of anti-SARS-CoV-2 vaccines and therapeutics.
最近爆发的严重急性呼吸综合征冠状病毒 2 型（SARS-CoV-2）引发了全球卫生紧急事件。SARS-CoV-2 的三聚体刺突（S）糖蛋白与人血管紧张素转换酶 2（ACE2）受体相互作用，介导病毒进入宿主细胞。我们报告了冷冻电镜结构，分别解析了紧密关闭的 SARS-CoV-2 S 三聚体与包装的融合肽以及与 ACE2 结合的 S 三聚体的结构，分辨率分别为 2.7 Å 和 3.8 Å。伴随 ACE2 与受体结合结构域（RBD）结合，相关的 ACE2-RBD 表现出连续的摆动运动。值得注意的是，与 SARS-CoV S 三聚体相比，SARS-CoV-2 S 三聚体对于受体触发的从封闭前融合状态到融合倾向的开放状态的转变更为敏感，这可能导致 SARS-CoV-2 的感染性更强。我们定义了 RBD 的 T470-T478 环和 Y505 作为病毒决定簇，用于 ACE2 对 SARS-CoV-2 RBD 的特异性识别。我们的研究结果描绘了 ACE2 诱导 S 三聚体构象从基础前融合状态向融合后状态转变的机制，有助于开发针对 SARS-CoV-2 的疫苗和治疗方法。
