3U5J

Crystal Structure of the first bromodomain of human BRD4 in complex with Alprazolam

3U5J の概要

• エントリーDOI: 10.2210/pdb3u5j/pdb
• 関連するPDBエントリー: 3U5K 3U5L
• 分子名称: Bromodomain-containing protein 4, 8-chloro-1-methyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine, 1,2-ETHANEDIOL, ... (4 entities in total)
• 機能のキーワード: bromodomain-containing protein 4 isoform long, brd4, bromodomain containing protein 4, cap, hunk1, mcap, mitotic chromosome associated protein, structural genomics consortium, sgc, signaling protein-inhibitor complex, signaling protein/inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Nucleus (By similarity): O60885
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 15656.42

構造登録者

Filippakopoulos, P.,Picaud, S.,Felletar, I.,Fedorov, O.,von Delft, F.,Arrowsmith, C.H.,Edwards, A.M.,Weigelt, J.,Bountra, C.,Knapp, S.,Structural Genomics Consortium (SGC) (登録日: 2011-10-11, 公開日: 2011-11-23, 最終更新日: 2023-09-13)

主引用文献

Filippakopoulos, P.,Picaud, S.,Fedorov, O.,Keller, M.,Wrobel, M.,Morgenstern, O.,Bracher, F.,Knapp, S.
Benzodiazepines and benzotriazepines as protein interaction inhibitors targeting bromodomains of the BET family.
Bioorg.Med.Chem., 20:1878-1886, 2012

PubMed Abstract: Benzodiazepines are psychoactive drugs with anxiolytic, sedative, skeletal muscle relaxant and amnestic properties. Recently triazolo-benzodiazepines have been also described as potent and highly selective protein interaction inhibitors of bromodomain and extra-terminal (BET) proteins, a family of transcriptional co-regulators that play a key role in cancer cell survival and proliferation, but the requirements for high affinity interaction of this compound class with bromodomains has not been described. Here we provide insight into the structure-activity relationship (SAR) and selectivity of this versatile scaffold. In addition, using high resolution crystal structures we compared the binding mode of a series of benzodiazepine (BzD) and related triazolo-benzotriazepines (BzT) derivatives including clinically approved drugs such as alprazolam and midazolam. Our analysis revealed the importance of the 1-methyl triazolo ring system for BET binding and suggests modifications for the development of further high affinity bromodomain inhibitors.

PubMed: 22137933
DOI: 10.1016/j.bmc.2011.10.080

実験手法

X-RAY DIFFRACTION (1.6 Å)