5N2D
Structure of PD-L1/small-molecule inhibitor complex
Summary for 5N2D
| Entry DOI | 10.2210/pdb5n2d/pdb |
| Descriptor | Programmed cell death 1 ligand 1, ~{N}-[2-[[2,6-dimethoxy-4-[(2-methyl-3-phenyl-phenyl)methoxy]phenyl]methylamino]ethyl]ethanamide (3 entities in total) |
| Functional Keywords | pd-l1, pd-1, small-molecule inhibitor, cell cycle |
| Biological source | Homo sapiens (Human) |
| Cellular location | Isoform 1: Cell membrane ; Single-pass type I membrane protein . Isoform 2: Endomembrane system ; Single-pass type I membrane protein : Q9NZQ7 |
| Total number of polymer chains | 4 |
| Total formula weight | 67834.12 |
| 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: 2024-10-16) |
| 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 Cited by 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: 28613862DOI: 10.1021/acs.jmedchem.7b00293 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.35 Å) |
Structure validation
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