3P5O

Crystal Structure of the First Bromodomain of Human Brd4 in complex with IBET inhibitor

3P5O の概要

• エントリーDOI: 10.2210/pdb3p5o/pdb
• 分子名称: Bromodomain-containing protein 4, 2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide, 1,2-ETHANEDIOL, ... (4 entities in total)
• 機能のキーワード: brd4, bromodomain containing protein 4, antagonist, ibet, inhibition of acetylated lysine histone binding, transcription regulator, 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: 15771.55

構造登録者

Chung, C. (登録日: 2010-10-09, 公開日: 2010-11-17, 最終更新日: 2023-11-01)

主引用文献

Nicodeme, E.,Jeffrey, K.L.,Schaefer, U.,Beinke, S.,Dewell, S.,Chung, C.,Chandwani, R.,Marazzi, I.,Wilson, P.,Coste, H.,White, J.,Kirilovsky, J.,Rice, C.M.,Lora, J.M.,Prinjha, R.K.,Lee, K.,Tarakhovsky, A.
Suppression of inflammation by a synthetic histone mimic
Nature, 468:1119-1123, 2010

PubMed Abstract: Interaction of pathogens with cells of the immune system results in activation of inflammatory gene expression. This response, although vital for immune defence, is frequently deleterious to the host due to the exaggerated production of inflammatory proteins. The scope of inflammatory responses reflects the activation state of signalling proteins upstream of inflammatory genes as well as signal-induced assembly of nuclear chromatin complexes that support mRNA expression. Recognition of post-translationally modified histones by nuclear proteins that initiate mRNA transcription and support mRNA elongation is a critical step in the regulation of gene expression. Here we present a novel pharmacological approach that targets inflammatory gene expression by interfering with the recognition of acetylated histones by the bromodomain and extra terminal domain (BET) family of proteins. We describe a synthetic compound (I-BET) that by 'mimicking' acetylated histones disrupts chromatin complexes responsible for the expression of key inflammatory genes in activated macrophages, and confers protection against lipopolysaccharide-induced endotoxic shock and bacteria-induced sepsis. Our findings suggest that synthetic compounds specifically targeting proteins that recognize post-translationally modified histones can serve as a new generation of immunomodulatory drugs.

PubMed: 21068722
DOI: 10.1038/nature09589

実験手法

X-RAY DIFFRACTION (1.6 Å)