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Updated: Feb 25, 2026
Identifying PD-1/PD-L1 Inhibitors with Surface Plasmon Resonance Technology
Published on: May 2, 2025
Structural Biology of the Immune Checkpoint Receptor PD-1 and Its Ligands PD-L1/PD-L2
Krzysztof M Zak1, Przemyslaw Grudnik1, Katarzyna Magiera2
1Malopolska Centre of Biotechnology, Jagiellonian University, Gronostajowa 7a, 30-387 Krakow, Poland; Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland.
Abstract:
Cancer cells can avoid and suppress immune responses through activation of inhibitory immune checkpoint proteins, such as PD-1, PD-L1, and CTLA-4. Blocking the activities of these proteins with monoclonal antibodies, and thus restoring T cell function, has delivered breakthrough therapies against cancer. In this review, we describe the latest work on structural characterization of the checkpoint proteins, their interactions with cognate ligands and with therapeutic antibodies. Structures of the extracellular portions of these proteins reveal that they all have a similar modular structure, composed of small domains similar in topology to the domains found in antibodies. Structural basis for blocking the PD-1/PD-L1 interaction by small molecules is illustrated with the compound BMS-202 that binds to and induces dimerization of PD-L1.
Insights
Immune checkpoint proteins like PD-1 and CTLA-4 help cancer cells evade immune responses. Blocking these proteins with antibodies or small molecules can restore T cell function and treat cancer.
Area of Science:
- Immunology
- Structural Biology
- Cancer Therapy
Background:
- Immune checkpoint proteins (e.g., PD-1, PD-L1, CTLA-4) are crucial for immune evasion by cancer cells.
- Monoclonal antibodies targeting these proteins have revolutionized cancer treatment by restoring T cell activity.
Purpose of the Study:
- To review the latest structural characterizations of immune checkpoint proteins.
- To elucidate the structural basis of their interactions with ligands and therapeutic antibodies.
- To explore small molecule inhibitors targeting these pathways.
Main Methods:
- Structural analysis of extracellular domains of checkpoint proteins.
- Investigation of protein-ligand interactions.
- Examination of antibody-protein binding interfaces.
- Case study of BMS-202's interaction with PD-L1.
Main Results:
- Checkpoint proteins share a conserved modular structure, resembling antibody domains.
- Structural insights into how antibodies block immune checkpoint interactions.
- Demonstration of small molecule BMS-202 binding to PD-L1, inducing dimerization.
Conclusions:
- Structural data provides a foundation for understanding checkpoint protein function and inhibition.
- Therapeutic antibodies effectively block inhibitory checkpoint signaling.
- Small molecules offer an alternative strategy for targeting immune checkpoints, exemplified by BMS-202.
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