1. Volume 25, Issue 8, Pages 1163-1174 (August 2017)
Structural Biology of the Immune Checkpoint Receptor PD-1 and Its Ligands PD-L1/PD- L2 
Krzysztof M. Zak, Przemyslaw Grudnik, Katarzyna Magiera, Alexander Dömling, Grzegorz Dubin, Tad A. Holak 
Structure 
Volume 25, Issue 8, Pages (August 2017)
DOI: /j.str
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2. Structure 2017 25, 1163-1174DOI: (10.1016/j.str.2017.06.011)
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3. Figure 1
Structures of Apo-Proteins of the PD-1/PD-L1 Checkpoint System
Subscripts refer to human (h) and murine (m) proteins.
(A) Superposition of human and murine PD-1.
(B) PD-L2.
(C) PD-L1.
See also Figures S1 and S2.
Structure  , DOI: ( /j.str )
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4. Figure 2 Structural Basis of the PD-1/PD-L1 (PD-L2) Interaction
PD-1/PD-L1 (A) and PD-1/PD-L2 (B) complexes (left panel) and close ups of their interaction surface (right panel). Analysis of the interaction surfaces of complexes demonstrates the primary hydrophobic nature of the contacts. Comparison of the key residues responsible for the interaction and their mutual disposition demonstrates small, but significant, differences within the PD-1/PD-L1 and PD-1/PD-L2 complexes. The major difference is visible for the tryptophan residue at the center of the interaction surface. The tryptophan side chain in PD-L1 is hidden inside the hydrophobic core of the protein and does not contribute to the interaction with PD-1. In contrast, the side chain of the Trp in PD-L2 is oriented toward the binding partner and participates in the interaction with the PD-1 protein.
See also Figures S2–S4.
Structure  , DOI: ( /j.str )
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5. Figure 3
Structural Basis for Blocking the PD-1/PD-L1 Interaction Using the Therapeutic Antibody Pembrolizumab
(A) Superposition of the full-length pembrolizumab structure (orange, blue) and pembrolizumab Fab (not shown) in complex with human PD-1 (green). The details of the interaction (two sub-interfaces with crucial residues) are magnified (sub-interface I and sub-interface II in the upper and lower panel, respectively).
(B) Superposition of PD-1/PD-L1 (green and red, respectively) and PD-1/pembrolizumab Fab (PD-1 is not shown; orange and light green, respectively) complexes. The PD-1 binding surface of PD-L1 overlaps with sub-interface II of pembrolizumab's antigen binding site, providing the rationale for the competition of the antibody and PD-L1 for the binding site on PD-1.
See also Table S1.
Structure  , DOI: ( /j.str )
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6. Figure 4
Interactions of PD-L1 with the PD-1 Receptor and Anti-PD-L1 Antibodies
(A) Structure of the fully human PD-1/PD-L1 complex. PD-1 is presented as a red ribbon, PD-L1 is presented as a gray surface. The PD-1 interaction surface is colored blue.
(B) PD-L1 surface representation, with the PD-1 interaction surface and shared regions targeted by antibodies colored in blue and yellow, respectively.
(C–F) PD-L1 surface representation, with the anti-PD-L1 antibody (durvalumab, avelumab, BMS , atezolizumab) interaction surfaces colored orange, magenta, cyan, and green, respectively. The shared regions targeted by the antibodies and PD-1 on the PD-L1 surface are presented in yellow. All representations are displayed in the same orientation. The PD-L1 molecule was derived from the fully human PD-1/PD-L1 complex.
See also Table S1.
Structure  , DOI: ( /j.str )
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7. Figure 5
Structural Basis for Blocking the PD-1/PD-L1 Interaction by Antibody and Small- Molecule Therapeutics Targeting PD-L1
(A) Crystal structure of the BMS Fab/PD-L1 complex (PDB: 5GGT).
(B) Crystal structure of the avelumab scFv/PD-L1 complex (PDB: 5GRJ).
(C) Small-molecule inhibitors of the PD-1/PD-L1 interaction. BMS-202 and BMS-8 bind PD-L1 in a similar manner; two PD-L1 molecules create a deep, hydrophobic cleft accommodating a single inhibitor molecule. General overview (left panel) and detailed interactions with key residues shown (right panel).
See also Figure S5, Table S1.
Structure  , DOI: ( /j.str )
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8. Figure 6
Structural Basis for Blocking the PD-1/PD-L1 Interaction by Different Antibodies
PD-1 is presented in gray and PD-L1 is presented in white. Colors present on the surfaces of both proteins (middle panel) correspond to the sites targeted by antibodies (bottom panel). Sites common for antibodies targeting PD-L1 are colored in brick-red (PD-L1 surface representation).
See also Table S1.
Structure  , DOI: ( /j.str )
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9. Figure 7
New Directions in Designing the Therapeutics Targeting the PD-1/PD-L1 Interaction
Structural insights with both therapeutic antibodies and small molecules have shown new potential hot spots located within PD-L1 loops. Moreover, available antibody/PD-L1 and small-molecule/PD-L1 complex structures indicate that PD-L1 surfaces may be targeted from different sites to abolish the PD-1/PD-L1 interaction.
(A) BMS-8/PD-L1 structure.
(B) Superposition of the KN035/PD-L1 and BMS-8/PD-L1 structures (only PD-L1B molecule is shown).
(C) Superposition of the avelumab/PD-L1 and BMS-8/PD-L1 structures (only PD-L1B molecule is shown).
(D) Superposition of the KN035/PD-L1, avelumab/PD-L1 and BMS-8/PD-L1 structures (only PD-L1B molecule is shown).
See also Table S1.
Structure  , DOI: ( /j.str )
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