7KO0

Crystal structure of the second bromodomain (BD2) of human BRD4 bound to SG3-179

7KO0 の概要

• エントリーDOI: 10.2210/pdb7ko0/pdb
• 分子名称: Bromodomain-containing protein 4, 4-[[4-[[3-(~{tert}-butylsulfonylamino)-4-chloranyl-phenyl]amino]-5-methyl-pyrimidin-2-yl]amino]-2-fluoranyl-~{N}-(1-methylpiperidin-4-yl)benzamide, 1,2-ETHANEDIOL, ... (4 entities in total)
• 機能のキーワード: bet, erk5, plk1, dual brd-kinase inhibitor, 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: 13773.42

構造登録者

Karim, M.R.,Zhu, J.Y.,Schonbrunn, E. (登録日: 2020-11-06, 公開日: 2021-10-20, 最終更新日: 2023-10-18)

主引用文献

Karim, R.M.,Bikowitz, M.J.,Chan, A.,Zhu, J.Y.,Grassie, D.,Becker, A.,Berndt, N.,Gunawan, S.,Lawrence, N.J.,Schonbrunn, E.
Differential BET Bromodomain Inhibition by Dihydropteridinone and Pyrimidodiazepinone Kinase Inhibitors.
J.Med.Chem., 64:15772-15786, 2021

PubMed Abstract: BRD4 and other members of the bromodomain and extraterminal (BET) family of proteins are promising epigenetic targets for the development of novel therapeutics. Among the reported BRD4 inhibitors are dihydropteridinones and benzopyrimidodiazepinones originally designed to target the kinases PLK1, ERK5, and LRRK2. While these kinase inhibitors were identified as BRD4 inhibitors, little is known about their binding potential and structural details of interaction with the other BET bromodomains. We comprehensively characterized a series of known and newly identified dual BRD4-kinase inhibitors against all eight individual BET bromodomains. A detailed analysis of 23 novel cocrystal structures of BET-kinase inhibitor complexes in combination with direct binding assays and cell signaling studies revealed significant differences in molecular shape complementarity and inhibitory potential. Collectively, the data offer new insights into the action of kinase inhibitors across BET bromodomains, which may aid the development of drugs to inhibit certain BET proteins and kinases differentially.

PubMed: 34710325
DOI: 10.1021/acs.jmedchem.1c01096

実験手法

X-RAY DIFFRACTION (1.9 Å)