6HOV

Crystal Structure of BRD4 first bromodomain in complex with ferulic acid

6HOV の概要

• エントリーDOI: 10.2210/pdb6hov/pdb
• 関連するPDBエントリー: 6HOQ
• 分子名称: Bromodomain-containing protein 4, 1,2-ETHANEDIOL, 3-(4-HYDROXY-3-METHOXYPHENYL)-2-PROPENOIC ACID, ... (4 entities in total)
• 機能のキーワード: four helical bundle, transcription
• 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: 15417.70

構造登録者

Dalle Vedove, A.,Lolli, G. (登録日: 2018-09-18, 公開日: 2019-10-09, 最終更新日: 2024-01-24)

主引用文献

Cozza, G.,Zonta, F.,Dalle Vedove, A.,Venerando, A.,Dall'Acqua, S.,Battistutta, R.,Ruzzene, M.,Lolli, G.
Biochemical and cellular mechanism of protein kinase CK2 inhibition by deceptive curcumin.
Febs J., 287:1850-1864, 2020

PubMed Abstract: Protein kinase CK2 is an antiapoptotic cancer-sustaining protein. Curcumin, reported previously as a CK2 inhibitor, is too bulky to be accommodated in the CK2 active site and rapidly degrades in solution generating various ATP-mimetic inhibitors; with a detailed comparative analysis, by means of both protein crystallography and enzymatic inhibition, ferulic acid was identified as the principal curcumin degradation product responsible for CK2 inhibition. The other curcumin derivatives vanillin, feruloylmethane and coniferyl aldehyde are weaker CK2 inhibitors. The high instability of curcumin in standard buffered solutions flags this compound, which is included in many commercial libraries, as a possible source of misleading interpretations, as was the case for CK2. Ferulic acid does not show any cytotoxicity and any inhibition of cellular CK2, due to its poor cellular permeability. However, curcumin acts as a prodrug in the cellular context, by generating its degradation products inside the treated cells, thus rescuing CK2 inhibition and consequently inducing cell death. Through the intracellular release of its degradation products, curcumin is expected to affect various target families; here, we identify the first bromodomain of BRD4 as a new target for those compounds. DATABASE: Structural data are available in the PDB database under the accession numbers 6HOP (CK2α/curcumin), 6HOQ (CK2α/ferulic acid), 6HOR (CK2α/feruloylmethane), 6HOT (CK2α/ferulic aldehyde), 6HOU (CK2α/vanillin) and 6HOV (BRD4/ferulic acid).

PubMed: 31661600
DOI: 10.1111/febs.15111

実験手法

X-RAY DIFFRACTION (1.85 Å)