Figure 4. Rationale for inhibition of PD-1/PD-L1 complex formation by BMS-202.

(A) BMS-202 induced PD-L1 dimer and PD-1/PD-L1 complex were superimposed such that a single molecule of PD-L1 (model A) within the BMS-202 (yellow) induced dimer (blue ribbon- model A, green surface – model B) was superposed with PD-L1 molecule (not shown) within PD-1/PD-L1 complex (PD-1 shown as red ribbon). Model B within PD-L1 dimer and PD-1 do not overlay perfectly (are shifted by around 10Å), but BMS-202 induced dimerization of PD-L1 masks almost the entire PD-1 interaction surface thereby preventing PD-1/PD-L1 interaction. Same is true for BMS-8 containing structure (not shown) (B) Superposition of the PD-L1 molecules extracted from apo-PD-L1 (orange ribbon; PDB 5C3T), PD-1/PD-L1 (PDB 4ZQK; PD-L1 shown as grey ribbon; PD-1 is not shown) and PD-L1/BMS-202 complex (model A shown as blue ribbon; BMS-202 shown as yellow sticks) structures demonstrates that PD-L1 does not undergo significant backbone rearrangement upon interaction with BMS-202. Model B of PD-L1/BMS-202 dimer is shown as green ribbon and surface. Same is true for BMS-8 containing structure (not shown).