Conformational dynamics of SARS-CoV-2 trimeric spike glycoprotein in complex with receptor ACE2 revealed by cryo-EM
Conformational dynamics of SARS-CoV-2 trimeric spike glycoprotein in complex with receptor ACE2 revealed by cryo-EM
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冷冻电镜揭示 SARS-CoV-2 三聚体刺突糖蛋白与受体 ACE2 复合物的构象动力学
DOI：
10.1101/2020.06.30.177097
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发表时间：
2020-06
期刊：
影响因子：
13.6
通讯作者：
Yao Cong
中科院分区：
文献类型：
--
作者：
Cong Xu;Yanxing Wang;Caixuan Liu;Chao Zhang;Wenyu Han;Xiaoyu Hong;Yifan Wang;Qin Hong;Shutian Wang;Qiaoyu Zhao;Yalei Wang;Yong Yang;Kaijian Chen;Wei Zheng;Liangliang kong;Fangfang Wang;Qinyu Zuo;Zhong Huang;Yao Cong
SARS-CoV-2刺突与ACE 2复合物的结构揭示了ACE 2诱导刺突构象转变的机制。最近爆发的SARS-CoV-2造成了全球卫生紧急情况。SARS-CoV-2三聚体刺突（S）糖蛋白与人ACE 2受体相互作用，介导病毒进入宿主细胞。我们报告了一个紧密封闭的SARS-CoV-2 S三聚体与包装的融合肽和ACE 2结合的S三聚体的冷冻电镜结构，分别在2.7和3.8倍分辨率。伴随着ACE 2与受体结合结构域（RBD）的结合，相关的ACE 2-RBD表现出连续的摆动运动。值得注意的是，SARS-CoV-2 S三聚体似乎对ACE 2受体比SARS-CoV S三聚体更敏感，这可能有助于SARS-CoV-2的上级感染性。我们将RBD T470-T478环和Y505定义为ACE 2特异性识别SARS-CoV-2 RBD的病毒决定簇。我们的研究结果描述了ACE 2诱导的S三聚体构象从融合前状态向融合后状态转变的机制，促进了抗SARS-CoV-2疫苗和治疗药物的开发。
Structure of SARS-CoV-2 spike in complex with ACE2 reveals the mechanism of ACE2 induced spike conformational transitions. 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.
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