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

作　　者：Renhong Yan Ruoke Wang Bin Ju Jinfang Yu Yuanyuan Zhang Nan Liu Jia Wang Qi Zhang Peng Chen Bing Zhou Yaning Li Yaping Shen Shuyuan Zhang Long Tian Yingying Guo Lu Xia Xinyue Zhong Lin Cheng Xiangyang Ge Juanjuan Zhao Hong-Wei Wang Xinquan Wang Zheng Zhang Linqi Zhang Qiang Zhou 

机构地区：[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,18 Shilongshan Road,Hangzhou,Zhejiang 310024,China [2]Institute of Biology,Westlake Institute for Advanced Study,18 Shilongshan Road,Hangzhou,Zhejiang 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

出　　处：《Cell Research》2021年第5期517-525,共9页细胞研究（英文版）

基　　金：We thank the cryo EM facility and the supercomputer center of Westlake University and the cryo-EM facility and the bio-computing platform at Tsinghua University Branch of China National Center for Protein Sciences(Beijing)for providing cryo-EM and computation supports.This work was funded by the National Natural Science Foundation of China(projects 32022037,82025022,31971123,81920108015,31930059,81530065,91442127,82002140);the SARS-CoV-2 emergency project of the Science and Technology Department of Zhejiang Province(2020C03129);the Key R&D Program of Zhejiang Province(2020C04001);the Beijing Advanced Innovation Center for Structural Biology and the National Key Plan for Scientific Research and Development of China(2020YFC0848800,2020YFC849900,2020YFC0844200);the Science and Technology Innovation Committee of Shenzhen Municipality(202002073000002,2020A1111350032,JCYJ20190809115617365,and 2020B1111340074);the Natural Science Foundation of Guangdong Province of China(2019A1515011197);Beijing Municipal Science and Technology Commission(Z201100005420019 and 171100000517);the Leading Innovative and Entrepreneur Team Introduction Program of Hangzhou,and Special Research Program of Novel Coronavirus Pneumonia of Westlake University and Tencent Foundation,Tsinghua University Spring Breeze Fund(2020Z99CFG004);The China Postdoctoral Science Foundation(2020M681937 to R.Y);the National Postdoctoral Program for Innovative Talents of China(BX20200304 to R.Y).

摘　　要：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.

关 键 词：ANTIBODIES NEUTRAL RESPIRATORY 

分 类 号：R373[医药卫生—病原生物学]