利用人血管紧张素转化酶 2 进入 SARS-CoV-2 的结构和功能基础

Structural and Functional Basis of SARS-CoV-2 Entry by Using Human ACE2.

机构信息

CAS Key Laboratory of Microbial Physiological and Metabolic Engineering, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; Shenzhen Key Laboratory of Pathogen and Immunity, Shenzhen Third People's Hospital, Shenzhen 518112, China; CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.

CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; University of the Chinese Academy of Sciences, Beijing 100049, China; Laboratory of Protein Engineering and Vaccines, Tianjin Institute of Biotechnology, Tianjin 300308, China.

出版信息

Cell. 2020 May 14;181(4):894-904.e9. doi: 10.1016/j.cell.2020.03.045. Epub 2020 Apr 9.

The recent emergence of a novel coronavirus (SARS-CoV-2) in China has caused significant public health concerns. Recently, ACE2 was reported as an entry receptor for SARS-CoV-2. In this study, we present the crystal structure of the C-terminal domain of SARS-CoV-2 (SARS-CoV-2-CTD) spike (S) protein in complex with human ACE2 (hACE2), which reveals a hACE2-binding mode similar overall to that observed for SARS-CoV. However, atomic details at the binding interface demonstrate that key residue substitutions in SARS-CoV-2-CTD slightly strengthen the interaction and lead to higher affinity for receptor binding than SARS-RBD. Additionally, a panel of murine monoclonal antibodies (mAbs) and polyclonal antibodies (pAbs) against SARS-CoV-S1/receptor-binding domain (RBD) were unable to interact with the SARS-CoV-2 S protein, indicating notable differences in antigenicity between SARS-CoV and SARS-CoV-2. These findings shed light on the viral pathogenesis and provide important structural information regarding development of therapeutic countermeasures against the emerging virus.

新型冠状病毒（SARS-CoV-2）在中国的出现引起了公众对健康的极大关注。最近，有报道称 ACE2 是 SARS-CoV-2 的进入受体。在这项研究中，我们展示了 SARS-CoV-2 刺突（S）蛋白 C 端结构域（SARS-CoV-2-CTD）与人类 ACE2（hACE2）复合物的晶体结构，揭示了一种总体上与 SARS-CoV 观察到的 hACE2 结合模式相似的结构。然而，结合界面的原子细节表明，SARS-CoV-2-CTD 中的关键残基取代略微增强了相互作用，导致对受体结合的亲和力高于 SARS-RBD。此外，针对 SARS-CoV-S1/受体结合域（RBD）的一组鼠单克隆抗体（mAbs）和多克隆抗体（pAbs）无法与 SARS-CoV-2 S 蛋白相互作用，表明 SARS-CoV 和 SARS-CoV-2 之间存在明显的抗原性差异。这些发现阐明了病毒发病机制，并为针对新兴病毒开发治疗对策提供了重要的结构信息。