5O4Y

Structure of human PD-L1 in complex with inhibitor

Summary for 5O4Y

• Entry DOI: 10.2210/pdb5o4y/pdb
• Descriptor: Programmed cell death 1 ligand 1, PHE-MAA-ASN-PRO-HIS-LEU-SER-TRP-SER-TRP-9KK-9KK-ARG-CCS-GLY-NH2 (3 entities in total)
• Functional Keywords: pd-1, programmed death 1, pd-l1, programmed death ligand 1, immune checkpoint, cancer, cell cycle
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 6
• Total formula weight: 45979.82

Authors

Magiera, K.,Grudnik, P.,Dubin, G.,Holak, T.A. (deposition date: 2017-05-31, release date: 2017-09-20, Last modification date: 2024-01-17)

Primary citation

Magiera-Mularz, K.,Skalniak, L.,Zak, K.M.,Musielak, B.,Rudzinska-Szostak, E.,Kocik, J.,Grudnik, P.,Sala, D.,Zarganes-Tzitzikas, T.,Shaabani, S.,Domling, A.,Dubin, G.,Holak, T.A.
Bioactive Macrocyclic Inhibitors of the PD-1/PD-L1 Immune Checkpoint.
Angew. Chem. Int. Ed. Engl., 56:13732-13735, 2017

PubMed Abstract: Blockade of the immunoinhibitory PD-1/PD-L1 pathway using monoclonal antibodies has shown impressive results with durable clinical antitumor responses. Anti-PD-1 and anti-PD-L1 antibodies have now been approved for the treatment of a number of tumor types, whereas the development of small molecules targeting immune checkpoints lags far behind. We characterized two classes of macrocyclic-peptide inhibitors directed at the PD-1/PD-L1 pathway. We show that these macrocyclic compounds act by directly binding to PD-L1 and that they are capable of antagonizing PD-L1 signaling and, similarly to antibodies, can restore the function of T-cells. We also provide the crystal structures of two of these small-molecule inhibitors bound to PD-L1. The structures provide a rationale for the checkpoint inhibition by these small molecules, and a description of their small molecule/PD-L1 interfaces provides a blueprint for the design of small-molecule inhibitors of the PD-1/PD-L1 pathway.

PubMed: 28881104
DOI: 10.1002/anie.201707707

Experimental method

X-RAY DIFFRACTION (2.3 Å)