4HBW

Crystal Structure of the first bromodomain of human BRD4 in complex with a quinazoline ligand

4HBW の概要

• エントリーDOI: 10.2210/pdb4hbw/pdb
• 関連するPDBエントリー: 4HBV 4HBX 4HBY
• 分子名称: Bromodomain-containing protein 4, 1,2-ETHANEDIOL, N-ethyl-3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide, ... (5 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, structural genomics consortium, sgc, protein binding/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: 15470.85

構造登録者

Filippakopoulos, P.,Picaud, S.,Qi, J.,Felletar, I.,von Delft, F.,Bountra, C.,Arrowsmith, C.H.,Edwards, A.,Fish, P.V.,Bunnage, M.E.,Cook, A.S.,Owen, D.R.,Knapp, S.,Structural Genomics Consortium (SGC) (登録日: 2012-09-28, 公開日: 2012-10-31, 最終更新日: 2023-09-20)

主引用文献

Fish, P.V.,Filippakopoulos, P.,Bish, G.,Brennan, P.E.,Bunnage, M.E.,Cook, A.S.,Federov, O.,Gerstenberger, B.S.,Jones, H.,Knapp, S.,Marsden, B.,Nocka, K.,Owen, D.R.,Philpott, M.,Picaud, S.,Primiano, M.J.,Ralph, M.J.,Sciammetta, N.,Trzupek, J.D.
Identification of a Chemical Probe for Bromo and Extra C-Terminal Bromodomain Inhibition through Optimization of a Fragment-Derived Hit.
J.Med.Chem., 55:9831-9837, 2012

PubMed Abstract: The posttranslational modification of chromatin through acetylation at selected histone lysine residues is governed by histone acetyltransferases (HATs) and histone deacetylases (HDACs). The significance of this subset of the epigenetic code is interrogated and interpreted by an acetyllysine-specific protein-protein interaction with bromodomain reader modules. Selective inhibition of the bromo and extra C-terminal domain (BET) family of bromodomains with a small molecule is feasible, and this may represent an opportunity for disease intervention through the recently disclosed antiproliferative and anti-inflammatory properties of such inhibitors. Herein, we describe the discovery and structure-activity relationship (SAR) of a novel, small-molecule chemical probe for BET family inhibition that was identified through the application of structure-based fragment assessment and optimization techniques. This has yielded a potent, selective compound with cell-based activity (PFI-1) that may further add to the understanding of BET family function within the bromodomains.

PubMed: 23095041
DOI: 10.1021/jm3010515

実験手法

X-RAY DIFFRACTION (1.69 Å)