An unexpected N-terminal loop in PD-1 dominates binding by nivolumab.
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.
CAS Key Laboratory of Microbial Physiological and Metabolic engineering, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.|CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
Shuguang
S
Tan
CAS Key Laboratory of Microbial Physiological and Metabolic engineering, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.|School of Life Sciences, Anhui University, Hefei 230601, China.
Hao
H
Zhang
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
Yan
Y
Chai
Research Network of Immunity and Health (RNIH), Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China.
Hao
H
Song
CAS Key Laboratory of Microbial Physiological and Metabolic engineering, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
Zhou
Z
Tong
CAS Key Laboratory of Microbial Physiological and Metabolic engineering, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
Qihui
Q
Wang
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
Jianxun
J
Qi
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
Gary
G
Wong
Beijing Combio Co., Ltd., Beijing 100111, China.
Xiaodong
X
Zhu
National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention (China CDC), Beijing 102206, China.
William J
WJ
Liu
CAS Key Laboratory of Bio-medical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou 215163, China.
Shan
S
Gao
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, Xi'an 710069, China.
Zhongfu
Z
Wang
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
Yi
Y
Shi
Laboratory of Protein and Peptide Pharmaceuticals &Laboratory of Proteomics, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Fuquan
F
Yang
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.|Research Network of Immunity and Health (RNIH), Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China.|National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention (China CDC), Beijing 102206, China.
George F
GF
Gao
CAS Key Laboratory of Microbial Physiological and Metabolic engineering, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.|CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.|School of Life Sciences, Anhui University, Hefei 230601, China.
Jinghua
J
Yan
D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized / Q000737:chemistry / Q000494:pharmacology; D000074322:Antineoplastic Agents, Immunological / Q000494:pharmacology*; D060890:B7-H1 Antigen / Q000378:metabolism*; D018360:Crystallography, X-Ray; D015195:Drug Design; D006031:Glycosylation; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D009369:Neoplasms / Q000188:drug therapy*; D000077594:Nivolumab; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D000072417:Protein Domains
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D060890:B7-H1 Antigen; C423236:CD274 protein, human; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D000077594:Nivolumab; C582435:pembrolizumab