(a) The apo PD-1 binding interface (Cheng et al., 2013), showing a flat, polar, core binding interface. Surface residues that shape the core binding interface are labelled. (b) The core PD-1 (green) - PD-L1 (yellow) binding interface, showing a flat hydrophobic receptor surface (Zak et al., 2015). White dashed lines indicate hydrogen bonds between PD-L1 side chains. (c) The core PD-1 (cyan) – PD-L2 (orange) binding interface, showing a large hydrophobic receptor cavity (Lázár-Molnár et al., 2008). White dashed lines indicate hydrogen bonds between PD-L2 side chains. Note that the conserved anchor residue Tyr123/112 is present in both (b) and (c). (d) Fractional occlusion of each bound-like Trp110 and Tyr123/112 atom position in the NMR ensemble of apo PD-1. Numerical values at each atom position denote the fraction of NMR frames that overlap, or ‘occlude’, that position (see Materials and methods for full details of how fractional occlusion is calculated). Aside from the Cβ, the Trp110 pocket is mostly occluded in the apo PD-1 ensemble, whereas the Tyr123/112 anchor pocket is largely open. (e) Overlay of apo, PD-L1–bound, and PD-L2–bound structures of PD-1 defining the ‘open’ and ‘closed’ states of PD-1 residues Asn66 and Ile126 in relation to the open and closed states of the Trp110 binding pocket.