6RPG

Structure of human Programmed cell death 1 ligand 1 (PD-L1) with inhibitor

Summary for 6RPG

• Entry DOI: 10.2210/pdb6rpg/pdb
• Descriptor: Programmed cell death 1 ligand 1, ~{N}-[2-[[4-[[3-[3-[[4-[(2-acetamidoethylamino)methyl]-5-[(5-cyanopyridin-3-yl)methoxy]-2-methyl-phenoxy]methyl]-2-methyl-phenyl]-2-methyl-phenyl]methoxy]-2-[(5-cyanopyridin-3-yl)methoxy]-5-methyl-phenyl]methylamino]ethyl]ethanamide (3 entities in total)
• Functional Keywords: complex, inhibitor, cell cycle
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 30272.61

Authors

Magiera-Mularz, K.,Basu, S.,Yang, J.,Xu, B.,Skalniak, L.,Musielak, B.,Kholodovych, V.,Holak, T.A.,Hu, L. (deposition date: 2019-05-14, release date: 2019-07-24, Last modification date: 2024-11-20)

Primary citation

Basu, S.,Yang, J.,Xu, B.,Magiera-Mularz, K.,Skalniak, L.,Musielak, B.,Kholodovych, V.,Holak, T.A.,Hu, L.
Design, Synthesis, Evaluation, and Structural Studies ofC2-Symmetric Small Molecule Inhibitors of Programmed Cell Death-1/Programmed Death-Ligand 1 Protein-Protein Interaction.
J.Med.Chem., 62:7250-7263, 2019

PubMed Abstract: A series of -symmetric inhibitors was designed and evaluated for inhibitory activity against the programmed cell death-1/programmed death-ligand 1(PD-1/PD-L1) protein-protein interaction (PPI) in a homogenous time-resolved fluorescence (HTRF) assay and PD-1 signaling in cell-based coculture assays. -symmetric inhibitors (LH1306) and (LH1307) exhibited IC values of 25 and 3.0 nM, respectively, in the HTRF assay. While was ∼3.8-fold more potent than previously reported inhibitor , could not be differentiated from due to their high potency and the limit of our HTRF assay conditions. In one cell-based coculture PD-1 signaling assay, and were 8.2- and 2.8-fold more potent in inhibiting PD-1 signaling than and , respectively. NMR and X-ray cocrystal structural studies provided more structural insights into the interaction between and PD-L1; binds to PD-L1 at the PD-1 binding site and induces the formation of a more symmetrically arranged PD-L1 homodimer than that previously reported for other inhibitors.

PubMed: 31298541
DOI: 10.1021/acs.jmedchem.9b00795

Experimental method

X-RAY DIFFRACTION (2.7 Å)