Structural Biology of the Immune Checkpoint Receptor PD-1 and Its Ligands PD-L1/PD-L2

Cancer cells often evade and suppress immune responses by activating inhibitory immune checkpoint proteins such as PD-1, PD-L1, and CTLA-4. Monoclonal antibodies that block these proteins and restore T cell function have led to significant advancements in cancer therapy. This review covers recent findings on the structural characterization of these checkpoint proteins, their interactions with their respective ligands, and their interactions with therapeutic antibodies. The extracellular regions of these checkpoint proteins have been shown to share a similar modular structure, with small domains that resemble the topology of antibody domains. Additionally, we highlight the structural basis for inhibiting the PD-1/PD-L1 interaction using small molecules, exemplified by BMS202, which binds to and induces dimerization of PD-L1.