4J1P

X-ray crystal structure of bromodomain 2 of human brd2 in complex with rvx208 to 1.08 A resolution

4J1P の概要

• エントリーDOI: 10.2210/pdb4j1p/pdb
• 関連するPDBエントリー: 4J3I
• 分子名称: Bromodomain containing 2, isoform CRA_a, 2-[4-(2-hydroxyethoxy)-3,5-dimethylphenyl]-5,7-dimethoxyquinazolin-4(3H)-one, 1,2-ETHANEDIOL, ... (4 entities in total)
• 機能のキーワード: brd2, bromodomain, signaling protein-inhibitor complex, signaling protein/inhibitor
• 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: 13807.88

構造登録者

Stein, A.J.,White, A.,Suto, R.K. (登録日: 2013-02-01, 公開日: 2014-01-15, 最終更新日: 2023-09-20)

主引用文献

McLure, K.G.,Gesner, E.M.,Tsujikawa, L.,Kharenko, O.A.,Attwell, S.,Campeau, E.,Wasiak, S.,Stein, A.,White, A.,Fontano, E.,Suto, R.K.,Wong, N.C.,Wagner, G.S.,Hansen, H.C.,Young, P.R.
RVX-208, an Inducer of ApoA-I in Humans, Is a BET Bromodomain Antagonist.
Plos One, 8:e83190-e83190, 2013

PubMed Abstract: Increased synthesis of Apolipoprotein A-I (ApoA-I) and HDL is believed to provide a new approach to treating atherosclerosis through the stimulation of reverse cholesterol transport. RVX-208 increases the production of ApoA-I in hepatocytes in vitro, and in vivo in monkeys and humans, which results in increased HDL-C, but the molecular target was not previously reported. Using binding assays and X-ray crystallography, we now show that RVX-208 selectively binds to bromodomains of the BET (Bromodomain and Extra Terminal) family, competing for a site bound by the endogenous ligand, acetylated lysine, and that this accounts for its pharmacological activity. siRNA experiments further suggest that induction of ApoA-I mRNA is mediated by BET family member BRD4. These data indicate that RVX-208 increases ApoA-I production through an epigenetic mechanism and suggests that BET inhibition may be a promising new approach to the treatment of atherosclerosis.

PubMed: 24391744
DOI: 10.1371/journal.pone.0083190

実験手法

X-RAY DIFFRACTION (1.08 Å)