Cell Reports (May 2022)
Structures of Omicron spike complexes and implications for neutralizing antibody development
- Hangtian Guo,
- Yan Gao,
- Tinghan Li,
- Tingting Li,
- Yuchi Lu,
- Le Zheng,
- Yue Liu,
- Tingting Yang,
- Feiyang Luo,
- Shuyi Song,
- Wei Wang,
- Xiuna Yang,
- Henry C. Nguyen,
- Hongkai Zhang,
- Ailong Huang,
- Aishun Jin,
- Haitao Yang,
- Zihe Rao,
- Xiaoyun Ji
Affiliations
- Hangtian Guo
- The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Institute of Viruses and Infectious Diseases, Chemistry and Biomedicine Innovation Center (ChemBIC), Institute of Artificial Intelligence Biomedicine, Nanjing University, Nanjing, China; Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China
- Yan Gao
- Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China; Shanghai Clinical Research and Trial Center, 201210 Shanghai, P.R. China
- Tinghan Li
- The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Institute of Viruses and Infectious Diseases, Chemistry and Biomedicine Innovation Center (ChemBIC), Institute of Artificial Intelligence Biomedicine, Nanjing University, Nanjing, China
- Tingting Li
- Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing 400010, China; Chongqing Key Laboratory of Basic and Translational Research of Tumor Immunology, Chongqing Medical University, Chongqing 400010, China
- Yuchi Lu
- Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China
- Le Zheng
- The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Institute of Viruses and Infectious Diseases, Chemistry and Biomedicine Innovation Center (ChemBIC), Institute of Artificial Intelligence Biomedicine, Nanjing University, Nanjing, China
- Yue Liu
- The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Institute of Viruses and Infectious Diseases, Chemistry and Biomedicine Innovation Center (ChemBIC), Institute of Artificial Intelligence Biomedicine, Nanjing University, Nanjing, China
- Tingting Yang
- The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Institute of Viruses and Infectious Diseases, Chemistry and Biomedicine Innovation Center (ChemBIC), Institute of Artificial Intelligence Biomedicine, Nanjing University, Nanjing, China
- Feiyang Luo
- Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing 400010, China; Chongqing Key Laboratory of Basic and Translational Research of Tumor Immunology, Chongqing Medical University, Chongqing 400010, China
- Shuyi Song
- Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing 400010, China; Chongqing Key Laboratory of Basic and Translational Research of Tumor Immunology, Chongqing Medical University, Chongqing 400010, China
- Wei Wang
- Institute of Life Sciences, Chongqing Medical University, Chongqing 400010, China
- Xiuna Yang
- Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China; Shanghai Clinical Research and Trial Center, 201210 Shanghai, P.R. China
- Henry C. Nguyen
- Asher Biotherapeutics, 650 Gateway Blvd, Suite 100, South San Francisco, CA 94080, USA
- Hongkai Zhang
- Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China; State Key Laboratory of Medicinal Chemical Biology and College of Life Sciences, Nankai University, Tianjin 300350, P.R. China
- Ailong Huang
- Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, Chongqing Medical University, Chongqing 400010, China; Corresponding author
- Aishun Jin
- Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing 400010, China; Chongqing Key Laboratory of Basic and Translational Research of Tumor Immunology, Chongqing Medical University, Chongqing 400010, China; Corresponding author
- Haitao Yang
- Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China; Shanghai Clinical Research and Trial Center, 201210 Shanghai, P.R. China; Corresponding author
- Zihe Rao
- Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China; Laboratory of Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing, China; Corresponding author
- Xiaoyun Ji
- The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Institute of Viruses and Infectious Diseases, Chemistry and Biomedicine Innovation Center (ChemBIC), Institute of Artificial Intelligence Biomedicine, Nanjing University, Nanjing, China; Institute of Life Sciences, Chongqing Medical University, Chongqing 400010, China; Engineering Research Center of Protein and Peptide Medicine, Ministry of Education, Nanjing, China; Corresponding author
- Journal volume & issue
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Vol. 39,
no. 5
p. 110770
Abstract
Summary: 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 SARS-CoV-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.
