Structure of the Complex of Human Programmed Death 1, PD-1, and Its Ligand PD-L1

Abstract

Targeting the PD-1/PD-L1 immunologic checkpoint with monoclonal antibodies has recently provided breakthrough progress in the treatment of melanoma, non-small cell lung cancer, and other types of cancer. Small-molecule drugs interfering with this pathway are highly awaited, but their development is hindered by insufficient structural information. This study reveals the molecular details of the human PD-1/PD-L1 interaction based on an X-ray structure of the complex. First, it is shown that the ligand binding to human PD-1 is associated with significant plasticity within the receptor. Second, a detailed molecular map of the interaction surface is provided, allowing definition of the regions within both interacting partners that may likely be targeted by small molecules.

Figure 1. Binding of hPD-L1 Induces Significant Structural Rearrangements within the Structure of hPD-1

Within the complex structure, hPD-1 is colored blue and hPD-L1 is colored green; both are shown in stereo view in ribbon representation. Apo-hPD1 (PDB: 3RRQ) was overlaid on hPD-1 within the complex, and residues 62–82 of the former are shown (yellow ribbon). The structural rearrangement within the CC′ loop upon complex formation is clearly discernible.

Figure 2. Close-Up Views of the hPD-1/hPD-L1 Interface

hPD-1 and hPD-L1 are represented by blue and green ribbons, respectively. All residues important for the interaction are highlighted as sticks. Residues forming the hydrophobic core are colored yellow. Water molecules are shown as red spheres. Hydrogen bonds are depicted as black dashed lines. (A) Front-side view. (B) Back-side view.

Figure 3. Gly124 Cleft (_LTyr123-Accommodating Cavity) and CC′ Loop Rearrangement Are Induced by hPD-L1 Binding to hPD-1

(A and B) Surface representation of the hPD-L1 binding site of hPD-1. (A) Apo-hPD-1. (B) hPD-1 complexed with hPD-L1. The CC′ loop is marked by the blue circle, the _LTyr123-accommodating cavity (i.e. the Gly124 cleft) is marked by a cyan circle; Tyr68 and Glu136 are marked in yellow and green, respectively. (C and D) Cross sections through CC′ loop (blue line) and Gly124 cleft (cyan line) of hPD-1 structures shown in (A) and (B), respectively, depicting rearrangement of the interaction surface upon ligand binding.

Figure 4. Three Main Hot Spots on the PD-L1 Surface

The deepest cleft comprises _LTyr56, _LGlu58, _LArg113, _LTyr123, and _LMet115. The second hot spot is formed by _LMet115, _LAla121, and _LTyr123. The third hot spot, constituted by a shallow groove, is composed of _LAsp122-_LArg125 and _LAsp26. Residues from hPD-1 are colored blue, hPD-L1 is represented by gray surface, and the hot spots are marked by yellow circles. General orientation of the PD-1/PD-L1 complex is represented in the bottom left corner.