6AJX
Crystal structure of BRD4 in complex with isoliquiritigenin in the absence of DMSO
Summary for 6AJX
| Entry DOI | 10.2210/pdb6ajx/pdb |
| Descriptor | Bromodomain-containing protein 4, 2',4,4'-TRIHYDROXYCHALCONE, SODIUM ION, ... (4 entities in total) |
| Functional Keywords | bromodomain, brd4, inhibitor, isoliquiritigenin, transcription |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 16462.79 |
| Authors | Yokoyama, T.,Matsumoto, K.,Nabeshima, Y.,Mizuguchi, M. (deposition date: 2018-08-28, release date: 2019-06-12, Last modification date: 2024-03-27) |
| Primary citation | Yokoyama, T.,Matsumoto, K.,Ostermann, A.,Schrader, T.E.,Nabeshima, Y.,Mizuguchi, M. Structural and thermodynamic characterization of the binding of isoliquiritigenin to the first bromodomain of BRD4. Febs J., 286:1656-1667, 2019 Cited by PubMed Abstract: Bromodomain-containing protein 4 (BRD4) recognizes the acetylated lysine of histone H4 via its bromodomains, leading to the recruitment of positive transcription elongation factor b. Small molecules that inhibit BRD4 have potential as anticancer agents by leading to the downregulation of specific oncogenes. Using X-ray crystallographic screening, we identified the BRD4 inhibitory activity of isoliquiritigenin (ISL), a natural chalcone found in licorice. Structural analysis revealed that ISL bound to BRD4 with a novel binding mode and squeezed out one of the six conserved water molecules that form a strong hydrogen bond network. The thermodynamic analysis revealed that the binding of ISL is enthalpy driven, suggesting that strong hydrogen bonds would compensate for the desolvation penalty. Neutron protein crystallography further suggested that the favorable binding enthalpy originates from the stabilization and optimization of the hydrogen bond network of the conserved water molecules. Here, we describe the novelty and potential of ISL as a template for new BRD4 inhibitors. PubMed: 30565859DOI: 10.1111/febs.14736 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.887 Å) |
Structure validation
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