Structures of Omicron spike complexes and implications for neutralizing antibody development

作者全名："Guo, Hangtian; Gao, Yan; Li, Tinghan; Li, Tingting; Lu, Yuchi; Zheng, Le; Liu, Yue; Yang, Tingting; Luo, Feiyang; Song, Shuyi; Wang, Wei; Yang, Xiuna; Nguyen, Henry C.; Zhang, Hongkai; Huang, Ailong; Jin, Aishun; Yang, Haitao; Rao, Zihe; Ji, Xiaoyun"

作者地址："[Guo, Hangtian; Li, Tinghan; Zheng, Le; Liu, Yue; Yang, Tingting; Ji, Xiaoyun] Nanjing Univ, Chem & Biomed Innovat Ctr ChemBIC, Sch Life Sci,Inst Artificial Intelligence Biomed, Inst Viruses & Infect Dis,State Key Lab Pharmaceu, Nanjing, Peoples R China; [Guo, Hangtian; Gao, Yan; Lu, Yuchi; Yang, Xiuna; Zhang, Hongkai; Yang, Haitao; Rao, Zihe] ShanghaiTech Univ, Shanghai Inst Adv Immunochem Studies, Shanghai, Peoples R China; [Guo, Hangtian; Gao, Yan; Lu, Yuchi; Yang, Xiuna; Zhang, Hongkai; Yang, Haitao; Rao, Zihe] ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China; [Gao, Yan; Yang, Xiuna; Yang, Haitao] Shanghai Clin Res & Trial Ctr, Shanghai 201210, Peoples R China; [Li, Tingting; Luo, Feiyang; Song, Shuyi; Jin, Aishun] Chongqing Med Univ, Coll Basic Med, Dept Immunol, Chongqing 400010, Peoples R China; [Li, Tingting; Luo, Feiyang; Song, Shuyi; Jin, Aishun] Chongqing Med Univ, Chongqing Key Lab Basic & Translat Res Tumor Immu, Chongqing 400010, Peoples R China; [Wang, Wei; Ji, Xiaoyun] Chongqing Med Univ, Inst Life Sci, Chongqing 400010, Peoples R China; [Nguyen, Henry C.] Asher Biotherapeut, 650 Gateway Blvd,Suite 100, San Francisco, CA 94080 USA; [Zhang, Hongkai] Nankai Univ, State Key Lab Med Chem Biol, Tianjin 300350, Peoples R China; [Zhang, Hongkai] Nankai Univ, Coll Life Sci, Tianjin 300350, Peoples R China; [Huang, Ailong] Chongqing Med Univ, Key Lab Mol Biol Infect Dis, Minist Educ, Chongqing 400010, Peoples R China; [Rao, Zihe] Tsinghua Univ, Sch Life Sci, Lab Struct Biol, Beijing, Peoples R China; [Rao, Zihe] Tsinghua Univ, Sch Med, Beijing, Peoples R China; [Ji, Xiaoyun] Minist Educ, Engn Res Ctr Prot & Peptide Med, Nanjing, Peoples R China"

通信作者："Ji, XY (通讯作者)，Nanjing Univ, Chem & Biomed Innovat Ctr ChemBIC, Sch Life Sci,Inst Artificial Intelligence Biomed, Inst Viruses & Infect Dis,State Key Lab Pharmaceu, Nanjing, Peoples R China.; Yang, HT; Rao, ZH (通讯作者)，ShanghaiTech Univ, Shanghai Inst Adv Immunochem Studies, Shanghai, Peoples R China.; Yang, HT; Rao, ZH (通讯作者)，ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China.; Yang, HT (通讯作者)，Shanghai Clin Res & Trial Ctr, Shanghai 201210, Peoples R China.; Jin, AS (通讯作者)，Chongqing Med Univ, Coll Basic Med, Dept Immunol, Chongqing 400010, Peoples R China.; Jin, AS (通讯作者)，Chongqing Med Univ, Chongqing Key Lab Basic & Translat Res Tumor Immu, Chongqing 400010, Peoples R China.; Ji, XY (通讯作者)，Chongqing Med Univ, Inst Life Sci, Chongqing 400010, Peoples R China.; Huang, AL (通讯作者)，Chongqing Med Univ, Key Lab Mol Biol Infect Dis, Minist Educ, Chongqing 400010, Peoples R China.; Rao, ZH (通讯作者)，Tsinghua Univ, Sch Life Sci, Lab Struct Biol, Beijing, Peoples R China.; Rao, ZH (通讯作者)，Tsinghua Univ, Sch Med, Beijing, Peoples R China.; Ji, XY (通讯作者)，Minist Educ, Engn Res Ctr Prot & Peptide Med, Nanjing, Peoples R China."

来源：CELL REPORTS

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:000801203900003

JCR分区：Q1

影响因子：8.8

年份：2022

卷号：39

期号：5

开始页：　

结束页：　

文献类型：Article

关键词：　

摘要："The emergence of the SARS-CoV-2 Omicron variant is dominant in many countries worldwide. The high number of spike mutations is responsible for the broad immune evasion from existing vaccines and antibody drugs. To understand this, we first present the cryo-electron microscopy structure of ACE2-bound SARSCoV-2 Omicron spike. Comparison to previous spike antibody structures explains how Omicron escapes these therapeutics. Secondly, we report structures of Omicron, Delta, and wild-type spikes bound to a patient-derived Fab antibody fragment (510A5), which provides direct evidence where antibody binding is greatly attenuated by the Omicron mutations, freeing spike to bind ACE2. Together with biochemical binding and 510A5 neutralization assays, our work establishes principles of binding required for neutralization and clearly illustrates how the mutations lead to antibody evasion yet retain strong ACE2 interactions. Structural information on spike with both bound and unbound antibodies collectively elucidates potential strategies for generation of therapeutic antibodies."

基金机构："National Key Research and Development Program of China [2018YFA0507100, 2016YFD0500300]; National Natural Science Foundation of China [92169109, 81871639]; National Key R&D Program of China [2020YFA0707502]; Science and Technology Commission of Shanghai Municipality [YDZX20213100001556, 20XD1422900]; Shanghai Municipal Sci-ence and Technology Major Project [ZD2021CY001]; pro-gram for Innovative Talents and Entrepreneur in Jiangsu; Fundamental Research Funds for the Central Universities; Lingang Laboratory [LG202101-01-07]"

基金资助正文："We thank Dr. Lei Sun from The Fifth People?s Hospital of Shanghai, Fudan Uni-versity, for the optimization guidance of spike protein expression and purifica-tion. We thank Dr. Yan Sun from Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, for SPR data collection and analysis. We thank Dr. Kailin Yang for his valuable discussions. We thank the Bio-Electron Micro-scopy Facility of ShanghaiTech University, and we are grateful to Dr. Qianqian Sun, Zhihui Zhang and Yaping Wang for their help with cryo-EM technical sup-port. This work was supported by funds from the National Key Research and Development Program of China (2018YFA0507100, 2016YFD0500300 to X.J.) , National Natural Science Foundation of China (grant No. 81871639 to X.J.) , National Key R&D Program of China (grant No. 2020YFA0707502 to H.Y.) , Lingang Laboratory (grant No. LG202101-01-07 to H.Y.) , Science and Technology Commission of Shanghai Municipality (grant No. YDZX20213100001556 and 20XD1422900 to H.Y.) , National Natural Science Foundation of China (grant No. 92169109 to H.Y.) , Shanghai Municipal Sci-ence and Technology Major Project (grant no. ZD2021CY001 to H.Y.) , the pro-gram for Innovative Talents and Entrepreneur in Jiangsu, and the Fundamental Research Funds for the Central Universities."