Volume 31, No 5, May 2021

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 31 Issue 5, May 2021: 517-525   |  Open Access

ORIGINAL ARTICLES

Structural basis for bivalent binding and inhibition of SARS-CoV-2 infection by human potent neutralizing antibodies

Renhong Yan^1,2 , Ruoke Wang^3,4 , Bin Ju^5,6 , Jinfang Yu^7,8,9,10 , Yuanyuan Zhang^1,2 , Nan Liu^4,7,8,10 , Jia Wang^4,7,8,11 , Qi Zhang³ , Peng Chen³ , Bing Zhou^5,6 , Yaning Li^4,8,10 , Yaping Shen^1,2 , Shuyuan Zhang^7,8,9,10 , Long Tian^7,8,9,10 , Yingying Guo^1,2 , Lu Xia^1,2 , Xinyue Zhong^1,2 , Lin Cheng⁵ , Xiangyang Ge⁵ , Juanjuan Zhao^5,11 , Hong-Wei Wang^7,10 , Xinquan Wang^7,8,9,10 , Zheng Zhang^5,6,* , Linqi Zhang^3,* , Qiang Zhou^1,2,*

¹Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, 18 Shilongshan Road, Hangzhou, Zhejiang 310024, China
²Institute of Biology, Westlake Institute for Advanced Study, 18 Shilongshan Road, Hangzhou, Zhejiang 310024, China
³Comprehensive AIDS Research Center and Beijing Advanced Innovation Center for Structural Biology, School of Medicine, and Vanke School of Public Health, Tsinghua University, Beijing 100084, China
⁴Tsinghua-Peking Joint Center for Life Sciences, Beijing 100084, China
⁵Institute for Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People’s Hospital, Shenzhen 518112, China
⁶The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology, Shenzhen 518055, China
⁷The Ministry of Education Key Laboratory of Protein Science, Beijing Frontier Research Center for Biological Structure, Beijing 100084, China
⁸Beijing Advanced Innovation Center for Structural Biology, Beijing Frontier Research Center for Biological Structure, Beijing 100084, China
⁹Collaborative Innovation Center for Biotherapy, Tsinghua University, Beijing 100084, China
¹⁰School of Life Sciences, Tsinghua University, Beijing 100084, China
¹¹Shenzhen Bay Laboratory, Shenzhen, Guangdong 518055, China
These authors contributed equally: Renhong Yan, Ruoke Wang, Bin Ju, Jinfang Yu, Yuanyuan Zhang, Nan Liu These authors jointly supervised this work: Hong-Wei Wang, Xinquan Wang, Zheng Zhang, Linqi Zhang, Qiang Zhou Correspondence: Zheng Zhang(zhangzheng1975@aliyun.com)Linqi Zhang(zhanglinqi@tsinghua.edu.cn)Qiang Zhou(zhouqiang@westlake.edu.cn)

Neutralizing monoclonal antibodies (nAbs) to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) represent promising candidates for clinical intervention against coronavirus disease 2019 (COVID-19). We isolated a large number of nAbs from SARS-CoV-2-infected individuals capable of disrupting proper interaction between the receptor binding domain (RBD) of the viral spike (S) protein and the receptor angiotensin converting enzyme 2 (ACE2). However, the structural basis for their potent neutralizing activity remains unclear. Here, we report cryo-EM structures of the ten most potent nAbs in their native full-length IgG-form or in both IgG-form and Fab-form bound to the trimeric S protein of SARS-CoV-2. The bivalent binding of the full-length IgG is found to associate with more RBDs in the “up” conformation than the monovalent binding of Fab, perhaps contributing to the enhanced neutralizing activity of IgG and triggering more shedding of the S1 subunit from the S protein. Comparison of a large number of nAbs identified common and unique structural features associated with their potent neutralizing activities. This work provides a structural basis for further understanding the mechanism of nAbs, especially through revealing the bivalent binding and its correlation with more potent neutralization and the shedding of S1 subunit.

https://doi.org/10.1038/s41422-021-00487-9

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