7C2Z

Bromodomain-containing 4 BD1 in complex with 3',4',7,8-Tetrahydroxyflavone

7C2Z の概要

• エントリーDOI: 10.2210/pdb7c2z/pdb
• 分子名称: Bromodomain-containing protein 4, 2-[3,4-bis(oxidanyl)phenyl]-7,8-bis(oxidanyl)chromen-4-one, FORMIC ACID, ... (4 entities in total)
• 機能のキーワード: brd4, bd1, 3', 4', 7, 8- tetrahydroxyflavonoid, acute myeloid leukemia, c-myc, gene regulation
• 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: 15344.56

構造登録者

Li, J.,Zhu, J. (登録日: 2020-05-10, 公開日: 2021-05-12, 最終更新日: 2023-11-29)

主引用文献

Li, J.,Zou, W.,Yu, K.,Liu, B.,Liang, W.,Wang, L.,Lu, Y.,Jiang, Z.,Wang, A.,Zhu, J.
Discovery of the natural product 3',4',7,8-tetrahydroxyflavone as a novel and potent selective BRD4 bromodomain 2 inhibitor.
J Enzyme Inhib Med Chem, 36:903-913, 2021

PubMed Abstract: Bromodomain-containing protein 4 (BRD4) binds acetylated lysine residues on the N-terminal tails of histones through two bromodomains (BD1 and BD2) to regulate gene transcription. Inhibiting one or both of bromodomains resulted in different phenotypes, suggesting BD1 and BD2 may have different functions. Here we report the characterisation of a natural product 3',4',7,8-tetrahydroxyflavone as a novel and potent selective BRD4 inhibitor. The compound is 100-fold more selective for BRD4-BD2 (IC50 = 204 nM) than BRD4-BD1 (IC=17.9 µM). Co-crystal structures show 3',4',7,8-tetrahydroxyflavone binds to the acetylated lysine binding pocket of BRD4-BD1 or BRD4-BD2, but establishes more interactions with BRD4-BD2 than BRD4-BD1. Our data suggest 3',4',7,8-tetrahydroxyflavone as a potent selective inhibitor of BRD4-BD2 with a novel chemical scaffold. Given its distinct chemical structure from current BRD4 inhibitors, this compound may open the door for a novel class of anti-BRD4 inhibitors by serving as a lead compound.

PubMed: 33820450
DOI: 10.1080/14756366.2021.1906663

実験手法

X-RAY DIFFRACTION (1.3 Å)