8QAR
Crystal Structure of the first bromodomain of BRD4 in complex with acetyl-pyrrole derivative compound 98
Summary for 8QAR
| Entry DOI | 10.2210/pdb8qar/pdb |
| Related | 7QZB 8QAL 8QAN 8QAP |
| Descriptor | Bromodomain-containing protein 4, 3-methyl-1-[2-[4-[(4-methyl-1~{H}-pyrazol-3-yl)methyl]piperazin-1-yl]-1,3-thiazol-4-yl]-2,5,6,7-tetrahydroisoindol-4-one, 1,2-ETHANEDIOL, ... (4 entities in total) |
| Functional Keywords | four helical bundle, transcription |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 15634.05 |
| Authors | Dalle Vedove, A.,Cazzanelli, G.,Lolli, G. (deposition date: 2023-08-23, release date: 2024-09-11, Last modification date: 2025-03-26) |
| Primary citation | Cazzanelli, G.,Dalle Vedove, A.,Sbardellati, N.,Valer, L.,Caflisch, A.,Lolli, G. Enhanced cellular death in liver and breast cancer cells by dual BET/BRPF1 inhibitors. Protein Sci., 33:e5191-e5191, 2024 Cited by PubMed Abstract: The acetylpyrrole scaffold is an acetylated lysine mimic that has been previously explored to develop bromodomain inhibitors. When tested on the hepatoma cell line Huh7 and the breast cancer cell line MDA-MB-231, a few compounds in our acetylpyrrole-thiazole library induced peculiar morphological changes, progressively causing cell death at increasing concentrations. Their evaluation on a panel of human bromodomains revealed concurrent inhibition of BRPF1 and BET bromodomains. To dissect the observed cellular effects, the acetylpyrrole derivatives were compared to JQ1 and GSK6853, chemical probes for the bromodomains of BET and BRPF1, respectively. The appearance of neurite-like extrusions, accompanied by βIII-tubulin overexpression, is caused by BET inhibition, with limited effect on cellular viability. Conversely, interference with BRPF1 induces cellular death but not phenotypic alterations. Combined treatment with JQ1 and GSK6853 showed additivity in reducing cellular viability, comparably to the acetylpyrrole-thiazole-based BET/BRPF1 inhibitors. In addition, we determined the crystallographic structures of the BRD4 and BRPF1 bromodomains in complex with the acetylpyrrole-thiazole compounds. The binding modes in the two bromodomains show similar interactions for the acetylpyrrole and different orientations of the moiety that point to the rim of the acetyl-lysine pocket. PubMed: 39473021DOI: 10.1002/pro.5191 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.5 Å) |
Structure validation
Download full validation report
