5N2F

Structure of PD-L1/small-molecule inhibitor complex

Summary for 5N2F

• Entry DOI: 10.2210/pdb5n2f/pdb
• Descriptor: Programmed cell death 1 ligand 1, 4-[[4-[[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methyl-phenyl]methoxy]-2,5-bis(fluoranyl)phenyl]methylamino]-3-oxidanylidene-butanoic acid, ... (4 entities in total)
• Functional Keywords: pd-l1, pd-1, small-molecule inhibitor, immune system
• Biological source: Homo sapiens (Human); More
• Cellular location: Isoform 1: Cell membrane ; Single-pass type I membrane protein . Isoform 2: Endomembrane system ; Single-pass type I membrane protein : Q9NZQ7 Q9NZQ7
• Total number of polymer chains: 2
• Total formula weight: 29026.12

Authors

Guzik, K.,Zak, K.M.,Grudnik, P.,Dubin, G.,Holak, T.A. (deposition date: 2017-02-07, release date: 2017-06-28, Last modification date: 2024-11-13)

Primary citation

Guzik, K.,Zak, K.M.,Grudnik, P.,Magiera, K.,Musielak, B.,Torner, R.,Skalniak, L.,Domling, A.,Dubin, G.,Holak, T.A.
Small-Molecule Inhibitors of the Programmed Cell Death-1/Programmed Death-Ligand 1 (PD-1/PD-L1) Interaction via Transiently Induced Protein States and Dimerization of PD-L1.
J. Med. Chem., 60:5857-5867, 2017

PubMed Abstract: Blockade of the PD-1/PD-L1 immune checkpoint pathway with monoclonal antibodies has provided significant advances in cancer treatment. The antibody-based immunotherapies carry a number of disadvantages such as the high cost of the antibodies, their limited half-life, and immunogenicity. Development of small-molecule PD-1/PD-L1 inhibitors that could overcome these drawbacks is slow because of the incomplete structural information for this pathway. The first chemical PD-1/PD-L1 inhibitors have been recently disclosed by Bristol-Myers Squibb. Here we present NMR and X-ray characterization for the two classes of these inhibitors. The X-ray structures of the PD-L1/inhibitor complexes reveal one inhibitor molecule located at the center of the PD-L1 homodimer, filling a deep hydrophobic channel-like pocket between two PD-L1 molecules. Derivatives of (2-methyl-3-biphenylyl)methanol exhibit the structures capped on one side of the channel, whereas the compounds based on [3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylphenyl]methanol induce an enlarged interaction interface that results in the open "face-back" tunnel through the PD-L1 dimer.

PubMed: 28613862
DOI: 10.1021/acs.jmedchem.7b00293

Experimental method

X-RAY DIFFRACTION (1.7 Å)