An unexpected N-terminal loop in PD-1 dominates binding by nivolumab
| العنوان: | An unexpected N-terminal loop in PD-1 dominates binding by nivolumab |
|---|---|
| المؤلفون: | Xiaodong Zhu, Hao Song, Hao Zhang, Jinghua Yan, Fuquan Yang, Gary Wong, Jianxun Qi, Zhongfu Wang, Qihui Wang, Shuguang Tan, Shan Gao, Zhou Tong, Yan Chai, Yi Shi, William J. Liu, George F. Gao |
| المصدر: | Nature Communications, Vol 8, Iss 1, Pp 1-10 (2017) Nature Communications |
| بيانات النشر: | Nature Portfolio, 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | 0301 basic medicine, Glycosylation, medicine.drug_class, medicine.medical_treatment, Science, Protein domain, Programmed Cell Death 1 Receptor, Inhibitory molecules, General Physics and Astronomy, Pembrolizumab, Plasma protein binding, Biology, Monoclonal antibody, Antibodies, Monoclonal, Humanized, Crystallography, X-Ray, General Biochemistry, Genetics and Molecular Biology, B7-H1 Antigen, Article, Terminal loop, 03 medical and health sciences, Antineoplastic Agents, Immunological, Cancer immunotherapy, Protein Domains, Neoplasms, medicine, Humans, Multidisciplinary, Antibodies, Monoclonal, General Chemistry, 3. Good health, 030104 developmental biology, Nivolumab, Drug Design, Immunology, Cancer research, Immunotherapy, Protein Binding |
| الوصف: | 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. Programmed cell death 1 (PD-1) is a key target for cancer immunotherapy. Here the authors present the crystal structure of the extracellular PD-1 domain with the clinically approved monoclonal antibody nivolumab, which shows that the N-terminal PD-1 loop is crucial for antibody binding. |
| اللغة: | English |
| تدمد: | 2041-1723 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::352f489a69beb92f53dbe858d3ef2244Test https://doaj.org/article/c5339e61324843929579ea934d9f1b79Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....352f489a69beb92f53dbe858d3ef2244 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20411723 |
|---|