5WT9

Complex structure of PD-1 and nivolumab-Fab

Summary for 5WT9

• Entry DOI: 10.2210/pdb5wt9/pdb
• Descriptor: Heavy Chain of Nivolumab, Light Chain of Nivolumab, Programmed cell death protein 1, ... (5 entities in total)
• Functional Keywords: pd-1, nivolumab, immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 67537.26

Authors

Tan, S.,Zhang, H.,Chai, Y.,Song, H.,Tong, Z.,Wang, Q.,Qi, J.,Wong, G.,Zhu, X.,Liu, W.J.,Gao, S.,Wang, Z.,Shi, Y.,Yang, F.,Gao, G.F.,Yan, J. (deposition date: 2016-12-10, release date: 2017-02-15, Last modification date: 2024-10-23)

Primary citation

Tan, S.,Zhang, H.,Chai, Y.,Song, H.,Tong, Z.,Wang, Q.,Qi, J.,Wong, G.,Zhu, X.,Liu, W.J.,Gao, S.,Wang, Z.,Shi, Y.,Yang, F.,Gao, G.F.,Yan, J.
An unexpected N-terminal loop in PD-1 dominates binding by nivolumab.
Nat Commun, 8:14369-14369, 2017

PubMed 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.

PubMed: 28165004
DOI: 10.1038/ncomms14369

Experimental method

X-RAY DIFFRACTION (2.401 Å)