3U5L
Crystal Structure of the first bromodomain of human BRD4 in complex with a benzo-triazepine ligand (BzT-7)
Summary for 3U5L
| Entry DOI | 10.2210/pdb3u5l/pdb |
| Related | 3U5J 3U5K |
| Descriptor | Bromodomain-containing protein 4, 1,2-ETHANEDIOL, 8-chloro-1,4-dimethyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,3,4]benzotriazepine, ... (4 entities in total) |
| Functional Keywords | bromodomain-containing protein 4 isoform long, brd4, bromodomain containing protein 4, cap, hunk1, mcap, mitotic chromosome associated protein, structural genomics consortium, sgc, signaling protein-inhibitor complex, signaling protein/inhibitor |
| Biological source | Homo sapiens (human) |
| Cellular location | Nucleus (By similarity): O60885 |
| Total number of polymer chains | 1 |
| Total formula weight | 15485.23 |
| Authors | Filippakopoulos, P.,Picaud, S.,Felletar, I.,Fedorov, O.,von Delft, F.,Arrowsmith, C.H.,Edwards, A.M.,Weigelt, J.,Bountra, C.,Bracher, F.,Knapp, S.,Structural Genomics Consortium (SGC) (deposition date: 2011-10-11, release date: 2011-11-23, Last modification date: 2023-09-13) |
| Primary citation | Filippakopoulos, P.,Picaud, S.,Fedorov, O.,Keller, M.,Wrobel, M.,Morgenstern, O.,Bracher, F.,Knapp, S. Benzodiazepines and benzotriazepines as protein interaction inhibitors targeting bromodomains of the BET family. Bioorg.Med.Chem., 20:1878-1886, 2012 Cited by PubMed Abstract: Benzodiazepines are psychoactive drugs with anxiolytic, sedative, skeletal muscle relaxant and amnestic properties. Recently triazolo-benzodiazepines have been also described as potent and highly selective protein interaction inhibitors of bromodomain and extra-terminal (BET) proteins, a family of transcriptional co-regulators that play a key role in cancer cell survival and proliferation, but the requirements for high affinity interaction of this compound class with bromodomains has not been described. Here we provide insight into the structure-activity relationship (SAR) and selectivity of this versatile scaffold. In addition, using high resolution crystal structures we compared the binding mode of a series of benzodiazepine (BzD) and related triazolo-benzotriazepines (BzT) derivatives including clinically approved drugs such as alprazolam and midazolam. Our analysis revealed the importance of the 1-methyl triazolo ring system for BET binding and suggests modifications for the development of further high affinity bromodomain inhibitors. PubMed: 22137933DOI: 10.1016/j.bmc.2011.10.080 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.39 Å) |
Structure validation
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