6MH7
Crystal structure of the first bromodomain of human BRD4 in complex with SKT-68, a 1,4,5-trisubstituted imidazole analogue
Summary for 6MH7
| Entry DOI | 10.2210/pdb6mh7/pdb |
| Descriptor | Bromodomain-containing protein 4, N-(3,4-dimethylphenyl)-4-[4-(4-fluorophenyl)-1-(piperidin-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine, DIMETHYL SULFOXIDE, ... (5 entities in total) |
| Functional Keywords | bromodomain, cap, hunk1, mcap, protein binding-inhibitor complex, inhibitor, transcription-inhibitor complex, inflammation, 19f-nmr, map-kinase inhibition, protein binding/inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 31410.23 |
| Authors | Zhu, J.-Y.,Schonbrunn, E. (deposition date: 2018-09-17, release date: 2019-08-07, Last modification date: 2023-10-11) |
| Primary citation | Divakaran, A.,Talluri, S.K.,Ayoub, A.M.,Mishra, N.K.,Cui, H.,Widen, J.C.,Berndt, N.,Zhu, J.Y.,Carlson, A.S.,Topczewski, J.J.,Schonbrunn, E.K.,Harki, D.A.,Pomerantz, W.C.K. Molecular Basis for the N-Terminal Bromodomain-and-Extra-Terminal-Family Selectivity of a Dual Kinase-Bromodomain Inhibitor. J.Med.Chem., 61:9316-9334, 2018 Cited by PubMed Abstract: As regulators of transcription, epigenetic proteins that interpret post-translational modifications to N-terminal histone tails are essential for maintaining cellular homeostasis. When dysregulated, "reader" proteins become drivers of disease. In the case of bromodomains, which recognize N-ε-acetylated lysine, selective inhibition of individual bromodomain-and-extra-terminal (BET)-family bromodomains has proven challenging. We describe the >55-fold N-terminal-BET bromodomain selectivity of 1,4,5-trisubstituted-imidazole dual kinase-bromodomain inhibitors. Selectivity for the BRD4 N-terminal bromodomain (BRD4(1)) over its second bromodomain (BRD4(2)) arises from the displacement of ordered waters and the conformational flexibility of lysine-141 in BRD4(1). Cellular efficacy was demonstrated via reduction of c-Myc expression, inhibition of NF-κB signaling, and suppression of IL-8 production through potential synergistic inhibition of BRD4(1) and p38α. These dual inhibitors provide a new scaffold for domain-selective inhibition of BRD4, the aberrant function of which plays a key role in cancer and inflammatory signaling. PubMed: 30253095DOI: 10.1021/acs.jmedchem.8b01248 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.74 Å) |
Structure validation
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