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

Yan，Renhong1,2; Wang，Ruoke3,4; Ju，Bin5,6; Yu，Jinfang7,8,9,10; Zhang，Yuanyuan1,2; Liu，Nan4,7,8,10; Wang，Jia4,7,8,10; Zhang，Qi3; Chen，Peng3; Zhou，Bing5,6; Li，Yaning4,8,10; Shen，Yaping1,2; Zhang，Shuyuan7,8,9,10; Tian，Long7,8,9,10; Guo，Yingying1,2; Xia，Lu1,2; Zhong，Xinyue1,2; Cheng，Lin5; Ge，Xiangyang5; Zhao，Juanjuan5,11; Wang，Hong Wei4,7,8,10; Wang，Xinquan7,8,9,10; Zhang，Zheng5,6; Zhang，Linqi3; Zhou，Qiang1,2

2021

10.1038/s41422-021-00487-9

CELL RESEARCH   影响因子和分区

1001-0602

1748-7838

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.

SCI

英语

其他

National Natural Science Foundation of China[32022037,82025022,31971123,81920108015,31930059,81530065,91442127,82002140] ; SARS-CoV-2 emergency project of the Science and Technology Department of Zhejiang Province[2020C03129] ; Key R&D Program of Zhejiang Province[2020C04001] ; National Key Plan for Scientific Research and Development of China["2020YFC0848800","2020YFC849900","2020YFC0844200"] ; Science and Technology Innovation Committee of Shenzhen Municipality[202002073000002,"2020A1111350032","JCYJ20190809115617365","2020B1111340074"] ; Natural Science Foundation of Guangdong Province of China[2019A1515011197] ; Beijing Municipal Science and Technology Commission["Z201100005420019",171100000517] ; Tsinghua University Spring Breeze Fund[2020Z99CFG004] ; China Postdoctoral Science Foundation[2020M681937] ; National Postdoctoral Program for Innovative Talents of China[BX20200304]

Cell Biology

Cell Biology

WOS:000629859000001

SPRINGERNATURE

MOLECULAR BIOLOGY & GENETICS

2-s2.0-85102998484

Scopus

1.Center 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,Hangzhou,18 Shilongshan Road,310024,China
2.Institute of Biology,Westlake Institute for Advanced Study,Hangzhou,18 Shilongshan Road,310024,China
3.Comprehensive 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
4.Tsinghua-Peking Joint Center for Life Sciences,Beijing,100084,China
5.Institute for Hepatology,National Clinical Research Center for Infectious Disease,Shenzhen Third People’s Hospital,Shenzhen,518112,China
6.The Second Affiliated Hospital,School of Medicine,Southern University of Science and Technology,Shenzhen,518055,China
7.The Ministry of Education Key Laboratory of Protein Science,Beijing Frontier Research Center for Biological Structure,Beijing,100084,China
8.Beijing Advanced Innovation Center for Structural Biology,Beijing Frontier Research Center for Biological Structure,Beijing,100084,China
9.Collaborative Innovation Center for Biotherapy,Tsinghua University,Beijing,100084,China
10.School of Life Sciences,Tsinghua University,Beijing,100084,China
11.Shenzhen Bay Laboratory,Shenzhen,Guangdong,518055,China

Yan，Renhong,Wang，Ruoke,Ju，Bin,et al. Structural basis for bivalent binding and inhibition of SARS-CoV-2 infection by human potent neutralizing antibodies[J]. CELL RESEARCH,2021.

Yan，Renhong.,Wang，Ruoke.,Ju，Bin.,Yu，Jinfang.,Zhang，Yuanyuan.,...&Zhou，Qiang.(2021).Structural basis for bivalent binding and inhibition of SARS-CoV-2 infection by human potent neutralizing antibodies.CELL RESEARCH.

Yan，Renhong,et al."Structural basis for bivalent binding and inhibition of SARS-CoV-2 infection by human potent neutralizing antibodies".CELL RESEARCH (2021).