2YEM

Crystal Structure of the Second Bromodomain of Human Brd4 with the inhibitor GW841819X

2YEM の概要

• エントリーDOI: 10.2210/pdb2yem/pdb
• 関連するPDBエントリー: 2YEK 2YEL
• 分子名称: BROMODOMAIN-CONTAINING PROTEIN 4, BENZYL [(4R)-1-METHYL-6-PHENYL-4H-[1,2,4]TRIAZOLO[4,3-A][1,4]BENZODIAZEPIN-4-YL]CARBAMATE (3 entities in total)
• 機能のキーワード: signaling protein, histone, epigenetic reader
• 由来する生物種: HOMO SAPIENS (HUMAN)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 30967.60

構造登録者

Chung, C.W. (登録日: 2011-03-25, 公開日: 2011-06-15, 最終更新日: 2023-12-20)

主引用文献

Chung, C.W.,Coste, H.,White, J.H.,Mirguet, O.,Wilde, J.,Gosmini, R.L.,Delves, C.,Magny, S.M.,Woodward, R.,Hughes, S.A.,Boursier, E.V.,Flynn, H.,Bouillot, A.M.,Bamborough, P.,Brusq, J.M.,Gellibert, F.J.,Jones, E.J.,Riou, A.M.,Homes, P.,Martin, S.L.,Uings, I.J.,Toum, J.,Clement, C.A.,Boullay, A.B.,Grimley, R.L.,Blandel, F.M.,Prinjha, R.K.,Lee, K.,Kirilovsky, J.,Nicodeme, E.
Discovery and Characterization of Small Molecule Inhibitors of the Bet Family Bromodomains.
J.Med.Chem., 54:3827-, 2011

PubMed Abstract: Epigenetic mechanisms of gene regulation have a profound role in normal development and disease processes. An integral part of this mechanism occurs through lysine acetylation of histone tails which are recognized by bromodomains. While the biological and structural characterization of many bromodomain containing proteins has advanced considerably, the therapeutic tractability of this protein family is only now becoming understood. This paper describes the discovery and molecular characterization of potent (nM) small molecule inhibitors that disrupt the function of the BET family of bromodomains (Brd2, Brd3, and Brd4). By using a combination of phenotypic screening, chemoproteomics, and biophysical studies, we have discovered that the protein-protein interactions between bromodomains and acetylated histones can be antagonized by selective small molecules that bind at the acetylated lysine recognition pocket. X-ray crystal structures of compounds bound into bromodomains of Brd2 and Brd4 elucidate the molecular interactions of binding and explain the precisely defined stereochemistry required for activity.

PubMed: 21568322
DOI: 10.1021/JM200108T

実験手法

X-RAY DIFFRACTION (2.3 Å)