4O70

Crystal structure of the first bromodomain of human BRD4 in complex with DINACICLIB

4O70 の概要

• エントリーDOI: 10.2210/pdb4o70/pdb
• 関連するPDBエントリー: 4O71 4O72 4O73 4O74 4O75 4O76 4O77 4O78 4O7A 4O7B 4O7C 4O7E 4O7F
• 分子名称: Bromodomain-containing protein 4, 3-[({3-ethyl-5-[(2S)-2-(2-hydroxyethyl)piperidin-1-yl]pyrazolo[1,5-a]pyrimidin-7-yl}amino)methyl]-1-hydroxypyridinium, 1,2-ETHANEDIOL, ... (4 entities in total)
• 機能のキーワード: bromodomain, cap, hunk1, mcap, protein binding-inhibitor complex, mitotic chromosome associated protein, cell cycle, inhibitor, transcription-inhibitor complex, transcription/inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Nucleus: O60885
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 31763.65

構造登録者

Ember, S.W.,Zhu, J.-Y.,Watts, C.,Schonbrunn, E. (登録日: 2013-12-24, 公開日: 2014-03-05, 最終更新日: 2023-09-20)

主引用文献

Ember, S.W.,Zhu, J.Y.,Olesen, S.H.,Martin, M.P.,Becker, A.,Berndt, N.,Georg, G.I.,Schonbrunn, E.
Acetyl-lysine Binding Site of Bromodomain-Containing Protein 4 (BRD4) Interacts with Diverse Kinase Inhibitors.
Acs Chem.Biol., 9:1160-1171, 2014

PubMed Abstract: Members of the bromodomain and extra terminal (BET) family of proteins are essential for the recognition of acetylated lysine (KAc) residues in histones and have emerged as promising drug targets in cancer, inflammation, and contraception research. In co-crystallization screening campaigns using the first bromodomain of BRD4 (BRD4-1) against kinase inhibitor libraries, we identified and characterized 14 kinase inhibitors (10 distinct chemical scaffolds) as ligands of the KAc binding site. Among these, the PLK1 inhibitor BI2536 and the JAK2 inhibitor TG101209 displayed strongest inhibitory potential against BRD4 (IC50=25 nM and 130 nM, respectively) and high selectivity for BET bromodomains. Comparative structural analysis revealed markedly different binding modes of kinase hinge-binding scaffolds in the KAc binding site, suggesting that BET proteins are potential off-targets of diverse kinase inhibitors. Combined, these findings provide a new structural framework for the rational design of next-generation BET-selective and dual-activity BET-kinase inhibitors.

PubMed: 24568369
DOI: 10.1021/cb500072z

実験手法

X-RAY DIFFRACTION (1.55 Å)