6SPX

Structure of protein kinase CK2 catalytic subunit in complex with the CK2beta-competitive bisubstrate inhibitor ARC1502

6SPX の概要

• エントリーDOI: 10.2210/pdb6spx/pdb
• 関連するPDBエントリー: 6SPW
• 分子名称: Casein kinase II subunit alpha, ARC1502, 8-[4,5,6,7-tetrakis(bromanyl)benzimidazol-1-yl]octanoic acid, ... (4 entities in total)
• 機能のキーワード: protein kinase ck2 casein kinase 2 bisubstrate inhibitor, transferase
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 41480.38

構造登録者

Niefind, K.,Schnitzler, A. (登録日: 2019-09-03, 公開日: 2020-01-29, 最終更新日: 2024-10-16)

主引用文献

Pietsch, M.,Viht, K.,Schnitzler, A.,Ekambaram, R.,Steinkruger, M.,Enkvist, E.,Nienberg, C.,Nickelsen, A.,Lauwers, M.,Jose, J.,Uri, A.,Niefind, K.
Unexpected CK2 beta-antagonistic functionality of bisubstrate inhibitors targeting protein kinase CK2.
Bioorg.Chem., 96:103608-103608, 2020

PubMed Abstract: Protein kinase CK2, a heterotetrameric holoenzyme composed of two catalytic chains (CK2α) attached to a homodimer of regulatory subunits (CK2β), is a target for drug development for cancer therapy. Here, we describe the tetraiodobenzimidazole derivative ARC-3140, a bisubstrate inhibitor addressing the ATP site and the substrate-binding site of CK2 with extraordinary affinity (K = 84 pM). In a crystal structure of ARC-3140 in complex with CK2α, three copies of the inhibitor are visible, one of them at the CK2β interface of CK2α. Subsequent interaction studies based on microscale thermophoresis and fluorescence anisotropy changes revealed a significant impact of ARC-3140 and of its tetrabromo equivalent ARC-1502 on the CK2α/CK2β interaction. A structural inspection revealed that ARC-3140, unlike CK2β antagonists described so far, interferes with both sub-interfaces of the bipartite CK2α/CK2β interaction. Thus, ARC-3140 is a lead for the further development of highly effective compounds perturbating the quaternary structure of the CK2αβ holoenzyme.

PubMed: 32058103
DOI: 10.1016/j.bioorg.2020.103608

実験手法

X-RAY DIFFRACTION (1.994 Å)