8R6Q

Co-crystal structure of PD-L1 with low molecular weight inhibitor

Summary for 8R6Q

• Entry DOI: 10.2210/pdb8r6q/pdb
• Descriptor: Programmed cell death 1 ligand 1, (3~{R})-1-[[4-[2-chloranyl-3-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl]-2-methoxy-phenyl]methyl]-~{N}-(2-hydroxyethyl)pyrrolidine-3-carboxamide, CHLORIDE ION, ... (5 entities in total)
• Functional Keywords: pd-l1, immunotherapy, smis, immune system
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 30143.57

Authors

Plewka, J.,Surmiak, E.,Magiera-Mularz, K.,Kalinowska-Tluscik, J. (deposition date: 2023-11-22, release date: 2024-01-17, Last modification date: 2024-11-13)

Primary citation

Surmiak, E.,Zaber, J.,Plewka, J.,Wojtanowicz, G.,Kocik-Krol, J.,Kruc, O.,Muszak, D.,Rodriguez, I.,Musielak, B.,Viviano, M.,Castellano, S.,Skalniak, L.,Magiera-Mularz, K.,Holak, T.A.,Kalinowska-Tluscik, J.
Solubilizer Tag Effect on PD-L1/Inhibitor Binding Properties for m -Terphenyl Derivatives.
Acs Med.Chem.Lett., 15:36-44, 2024

PubMed Abstract: Although heavily studied, the subject of anti-PD-L1 small-molecule inhibitors is still elusive. Here we present a systematic overview of the principles behind successful anti-PD-L1 small-molecule inhibitor design on the example of the -terphenyl scaffold, with a particular focus on the neglected influence of the solubilizer tag on the overall affinity toward PD-L1. The inhibitor developed according to the proposed guidelines was characterized through its potency in blocking PD-1/PD-L1 complex formation in homogeneous time-resolved fluorescence and cell-based assays. The affinity is also explained based on the crystal structure of the inhibitor itself and its costructure with PD-L1 as well as a molecular modeling study. Our results structuralize the knowledge related to the strong pharmacophore feature of the -terphenyl scaffold preferential geometry and the more complex role of the solubilizer tag in PD-L1 homodimer stabilization.

PubMed: 38229762
DOI: 10.1021/acsmedchemlett.3c00306

Experimental method

X-RAY DIFFRACTION (2.17 Å)