6r3k
Structure of human Programmed cell death 1 ligand 1 (PD-L1) with low molecular mass inhibitor
Structural highlights
FunctionPD1L1_HUMAN Involved in the costimulatory signal, essential for T-cell proliferation and production of IL10 and IFNG, in an IL2-dependent and a PDCD1-independent manner. Interaction with PDCD1 inhibits T-cell proliferation and cytokine production.[1] [2] Publication Abstract from PubMedWe describe a new class of potent PD-L1/PD-1 inhibitors based on a terphenyl scaffold that is derived from the rigidified biphenyl-inspired structure. Using in silico docking, we designed and then experimentally demonstrated the effectiveness of the terphenyl-based scaffolds in inhibiting PD-1/PD-L1 complex formation using various biophysical and biochemical techniques. We also present a high-resolution structure of the complex of PD-L1 with one of our most potent inhibitors to identify key PD-L1/inhibitor interactions at the molecular level. In addition, we show the efficacy of our most potent inhibitors in activating the antitumor response using primary human immune cells from healthy donors. Terphenyl-Based Small-Molecule Inhibitors of Programmed Cell Death-1/Programmed Death-Ligand 1 Protein-Protein Interaction.,Muszak D, Surmiak E, Plewka J, Magiera-Mularz K, Kocik-Krol J, Musielak B, Sala D, Kitel R, Stec M, Weglarczyk K, Siedlar M, Domling A, Skalniak L, Holak TA J Med Chem. 2021 Jul 27. doi: 10.1021/acs.jmedchem.1c00957. PMID:34313116[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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