8QAN

Crystal Structure of the first bromodomain of BRD4 in complex with acetyl-pyrrole derivative compound 79

8QAN の概要

• エントリーDOI: 10.2210/pdb8qan/pdb
• 関連するPDBエントリー: 7QYO 8QAL
• 分子名称: Bromodomain-containing protein 4, 1-[2-methyl-4-(3-methylbutyl)-5-(2-piperazin-1-yl-1,3-thiazol-4-yl)-1~{H}-pyrrol-3-yl]ethanone, 1,2-ETHANEDIOL, ... (4 entities in total)
• 機能のキーワード: four helical bundle, transcription
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 15521.96

構造登録者

Dalle Vedove, A.,Cazzanelli, G.,Lolli, G. (登録日: 2023-08-23, 公開日: 2024-09-11, 最終更新日: 2025-03-26)

主引用文献

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

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: 39473021
DOI: 10.1002/pro.5191

実験手法

X-RAY DIFFRACTION (1.25 Å)