Structure and Interactions of the Human Programmed Cell Death 1 Receptor

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