Journal of Biological Chemistry
Volume 288, Issue 17, 26 April 2013, Pages 11771-11785
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Immunology
Structure and Interactions of the Human Programmed Cell Death 1 Receptor*

https://doi.org/10.1074/jbc.M112.448126Get rights and content
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PD-1, a receptor expressed by T cells, B cells, and monocytes, is a potent regulator of immune responses and a promising therapeutic target. The structure and interactions of human PD-1 are, however, incompletely characterized. We present the solution nuclear magnetic resonance (NMR)-based structure of the human PD-1 extracellular region and detailed analyses of its interactions with its ligands, PD-L1 and PD-L2. PD-1 has typical immunoglobulin superfamily topology but differs at the edge of the GFCC′ sheet, which is flexible and completely lacks a C″ strand. Changes in PD-1 backbone NMR signals induced by ligand binding suggest that, whereas binding is centered on the GFCC′ sheet, PD-1 is engaged by its two ligands differently and in ways incompletely explained by crystal structures of mouse PD-1·ligand complexes. The affinities of these interactions and that of PD-L1 with the costimulatory protein B7-1, measured using surface plasmon resonance, are significantly weaker than expected. The 3–4-fold greater affinity of PD-L2 versus PD-L1 for human PD-1 is principally due to the 3-fold smaller dissociation rate for PD-L2 binding. Isothermal titration calorimetry revealed that the PD-1/PD-L1 interaction is entropically driven, whereas PD-1/PD-L2 binding has a large enthalpic component. Mathematical simulations based on the biophysical data and quantitative expression data suggest an unexpectedly limited contribution of PD-L2 to PD-1 ligation during interactions of activated T cells with antigen-presenting cells. These findings provide a rigorous structural and biophysical framework for interpreting the important functions of PD-1 and reveal that potent inhibitory signaling can be initiated by weakly interacting receptors.

Cell Surface Protein
Nuclear Magnetic Resonance
Receptors
Signaling
Surface Plasmon Resonance (SPR)
Affinity
Complex Formation
Thermodynamics

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The atomic coordinates and structure factors (code 2M2D) have been deposited in the Protein Data Bank (http://wwpdb.org/).

*

This work was supported by the Wellcome Trust, the United Kingdom Medical Research Council, UCB Celltech Ltd., and a grant from the G. Harold and Leila Y. Mathers Charitable Foundation (to J. E. L.).

This article contains supplemental Experimental Procedures and Table S1.

1

Both authors contributed equally to this work.