6KEC

Crystal structure of BRD4 bromodomain 1 (BD1) in complex with 4-ethoxy-5,16-dimethoxy-11-methyl-2-oxa-11-azatetracyclo[8.6.1.03,8.013,17]heptadeca-1(17),3,5,7,9,13,15-heptaen-12-one

6KEC の概要

• エントリーDOI: 10.2210/pdb6kec/pdb
• 分子名称: Bromodomain-containing protein 4, 4-ethoxy-5,16-dimethoxy-11-methyl-2-oxa-11-azatetracyclo[8.6.1.03,8.013,17]heptadeca-1(17),3,5,7,9,13,15-heptaen-12-one, FORMIC ACID, ... (4 entities in total)
• 機能のキーワード: brd4, bromodomain, 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: 15562.70

構造登録者

Lee, B.I.,Park, T.H. (登録日: 2019-07-04, 公開日: 2020-07-08, 最終更新日: 2023-11-22)

主引用文献

Yoo, M.,Park, T.H.,Yoo, M.,Kim, Y.,Lee, J.Y.,Lee, K.M.,Ryu, S.E.,Lee, B.I.,Jung, K.Y.,Park, C.H.
Synthesis and Structure-Activity Relationships of Aristoyagonine Derivatives as Brd4 Bromodomain Inhibitors with X-ray Co-Crystal Research.
Molecules, 26:-, 2021

PubMed Abstract: Epigenetic regulation is known to play a key role in progression of anti-cancer therapeutics. Lysine acetylation is an important mechanism in controlling gene expression. There has been increasing interest in bromodomain owing to its ability to modulate transcription of various genes as an epigenetic 'reader.' Herein, we report the design, synthesis, and X-ray studies of novel aristoyagonine (benzo[6,7]oxepino[4,3,2-]isoindol-2(1)-one) derivatives and investigate their inhibitory effect against Brd4 bromodomain. Five compounds , , , , and have been discovered with high binding affinity over the Brd4 protein. Co-crystal structures of these five inhibitors with human Brd4 bromodomain demonstrated that it has a key binding mode occupying the hydrophobic pocket, which is known to be the acetylated lysine binding site. These novel Brd4 bromodomain inhibitors demonstrated impressive inhibitory activity and mode of action for the treatment of cancer diseases.

PubMed: 33802888
DOI: 10.3390/molecules26061686

実験手法

X-RAY DIFFRACTION (1.35 Å)