An unexpected N-terminal loop in PD-1 dominates binding by nivolumab

Shuguang Tan, Hao Zhang, Yan Chai, Hao Song, Zhou Tong, Qihui Wang, Jianxun Qi, Gary Wong, Xiaodong Zhu, William J. Liu, Shan Gao, Zhongfu Wang, Yi Shi, Fuquan Yang, George F. Gao () and Jinghua Yan ()
Additional contact information
Shuguang Tan: CAS Key Laboratory of Microbial Physiological and Metabolic engineering, Institute of Microbiology, Chinese Academy of Sciences
Hao Zhang: CAS Key Laboratory of Microbial Physiological and Metabolic engineering, Institute of Microbiology, Chinese Academy of Sciences
Yan Chai: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences
Hao Song: Research Network of Immunity and Health (RNIH), Beijing Institutes of Life Science, Chinese Academy of Sciences
Zhou Tong: CAS Key Laboratory of Microbial Physiological and Metabolic engineering, Institute of Microbiology, Chinese Academy of Sciences
Qihui Wang: CAS Key Laboratory of Microbial Physiological and Metabolic engineering, Institute of Microbiology, Chinese Academy of Sciences
Jianxun Qi: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences
Gary Wong: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences
Xiaodong Zhu: Beijing Combio Co., Ltd.
William J. Liu: National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention (China CDC)
Shan Gao: CAS Key Laboratory of Bio-medical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences
Zhongfu Wang: Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education and Provincial Key Laboratory of Biotechnology, College of Life Sciences, Northwest University
Yi Shi: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences
Fuquan Yang: Laboratory of Protein and Peptide Pharmaceuticals & Laboratory of Proteomics, Institute of Biophysics, Chinese Academy of Sciences
George F. Gao: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences
Jinghua Yan: CAS Key Laboratory of Microbial Physiological and Metabolic engineering, Institute of Microbiology, Chinese Academy of Sciences

Nature Communications, 2017, vol. 8, issue 1, 1-10

Abstract: Abstract Cancer immunotherapy by targeting of immune checkpoint molecules has been a research ‘hot-spot’ in recent years. Nivolumab, a human monoclonal antibody targeting PD-1, has been widely used clinically since 2014. However, the binding mechanism of nivolumab to PD-1 has not yet been shown, despite a recent report describing the complex structure of pembrolizumab/PD-1. It has previously been speculated that PD-1 glycosylation is involved in nivolumab recognition. Here we report the complex structure of nivolumab with PD-1 and evaluate the effects of PD-1 N-glycosylation on the interactions with nivolumab. Structural and functional analyses unexpectedly reveal an N-terminal loop outside the IgV domain of PD-1. This loop is not involved in recognition of PD-L1 but dominates binding to nivolumab, whereas N-glycosylation is not involved in binding at all. Nivolumab binds to a completely different area than pembrolizumab. These results provide the basis for the design of future inhibitory molecules targeting PD-1.

Date: 2017
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DOI: 10.1038/ncomms14369

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