7MR8
Crystal structure of the first bromodomain (BD1) of human BRD4 bound to GXH-II-076
Summary for 7MR8
| Entry DOI | 10.2210/pdb7mr8/pdb |
| Descriptor | Bromodomain-containing protein 4, N-{3-[(2-{3-fluoro-4-[(piperidin-4-yl)carbamoyl]anilino}-5-methylpyrimidin-4-yl)amino]-5-[(2-methylpropane-2-sulfonyl)amino]benzoyl}-L-glutamic acid, 1,2-ETHANEDIOL, ... (4 entities in total) |
| Functional Keywords | bromosporine, brd4, brd, bet, gene regulation |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 15952.31 |
| Authors | Chan, A.,Schonbrunn, E. (deposition date: 2021-05-07, release date: 2022-05-11, Last modification date: 2026-07-29) |
| Primary citation | Liang, T.,Guan, X.,Chan, A.,Kalra, P.,Shi, R.,Solberg, J.,Sigua, L.H.,Qi, J.,Pomerantz, W.C.K.,Schonbrunn, E.,Hawkinson, J.E.,Georg, G.I. Structural Basis for BD1-Preferring 2,4-Disubstituted Pyrimidine BRDT Inhibitors. J.Med.Chem., 69:11088-11108, 2026 Cited by PubMed Abstract: The first bromodomain of the BET protein BRDT (BRDT-BD1) possesses a unique Arg54 residue at the terminus of the ZA channel, absent in other BET family members. We explored this structural uniqueness with 23 analogs of the BET/kinase inhibitor , each bearing an amino acid side chain to enable potential interactions between the positively charged arginine group and the negatively charged carboxylate groups. In an AlphaScreen assay, serine analog showed 35-fold selectivity for BRDT-T over BRD4-T. The BRDT-BD1 cocrystal structure with glutamic acid analog showed no interaction with Arg54, suggesting that the observed preference may be related to differences in the structured water molecules. Compound displayed exceptional in vitro metabolic stability but had limited cellular permeability in MDCK-MDR1 cells. Compounds and are among the best BRDT-BD1-preferring inhibitors reported to date and demonstrate a significant step toward identifying highly selective BRDT inhibitors for male contraception. PubMed: 41984625DOI: 10.1021/acs.jmedchem.6c00180 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.2 Å) |
Structure validation
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