4NUD

Crystal structure of the first bromodomain of human BRD4 in complex with MS436 inhibitor

4NUD の概要

• エントリーDOI: 10.2210/pdb4nud/pdb
• 関連するPDBエントリー: 4NUC 4NUE
• 分子名称: Bromodomain-containing protein 4, 4-[(E)-(2-amino-4-hydroxy-5-methylphenyl)diazenyl]-N-(pyridin-2-yl)benzenesulfonamide, 1,2-ETHANEDIOL, ... (4 entities in total)
• 機能のキーワード: transcription factor, transcription, transcription-transcription inhibitor complex, transcription/transcription inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Nucleus: O60885
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 15544.87

構造登録者

Plotnikov, A.N.,Joshua, J.,Zhou, M.-M. (登録日: 2013-12-03, 公開日: 2014-04-02, 最終更新日: 2024-02-28)

主引用文献

Zhang, G.,Plotnikov, A.N.,Rusinova, E.,Shen, T.,Morohashi, K.,Joshua, J.,Zeng, L.,Mujtaba, S.,Ohlmeyer, M.,Zhou, M.-M.
Structure-Guided Design of Potent Diazobenzene Inhibitors for the BET Bromodomains
J.Med.Chem., 56:9251-9264, 2013

PubMed Abstract: BRD4, characterized by two acetyl-lysine binding bromodomains and an extra-terminal (ET) domain, is a key chromatin organizer that directs gene activation in chromatin through transcription factor recruitment, enhancer assembly, and pause release of the RNA polymerase II complex for transcription elongation. BRD4 has been recently validated as a new epigenetic drug target for cancer and inflammation. Our current knowledge of the functional differences of the two bromodomains of BRD4, however, is limited and is hindered by the lack of selective inhibitors. Here, we report our structure-guided development of diazobenzene-based small-molecule inhibitors for the BRD4 bromodomains that have over 90% sequence identity at the acetyl-lysine binding site. Our lead compound, MS436, through a set of water-mediated interactions, exhibits low nanomolar affinity (estimated Ki of 30-50 nM), with preference for the first bromodomain over the second. We demonstrated that MS436 effectively inhibits BRD4 activity in NF-κB-directed production of nitric oxide and proinflammatory cytokine interleukin-6 in murine macrophages. MS436 represents a new class of bromodomain inhibitors and will facilitate further investigation of the biological functions of the two bromodomains of BRD4 in gene expression.

PubMed: 24144283

実験手法

X-RAY DIFFRACTION (1.2 Å)