7X4H

Crystal structure of CK2a1 complexed with AG1112

7X4H の概要

• エントリーDOI: 10.2210/pdb7x4h/pdb
• 分子名称: Casein Kinase 2 subunit alpha, 5-azanyl-3-[(~{Z})-1-cyano-2-(1~{H}-indol-3-yl)ethenyl]-1~{H}-pyrazole-4-carbonitrile (3 entities in total)
• 機能のキーワード: protein kinase, transferase
• 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: 41026.75

構造登録者

Ikeda, A.,Kinoshita, T.,Tsuyuguchi, M. (登録日: 2022-03-02, 公開日: 2023-01-18, 最終更新日: 2023-11-29)

主引用文献

Ikeda, A.,Tsuyuguchi, M.,Kitagawa, D.,Sawa, M.,Nakamura, S.,Nakanishi, I.,Kinoshita, T.
Bivalent binding mode of an amino-pyrazole inhibitor indicates the potentials for CK2 alpha 1-selective inhibitors.
Biochem.Biophys.Res.Commun., 630:30-35, 2022

PubMed Abstract: Casein kinase 2 (CK2) is a vital protein kinase that consists of two catalytic subunits (CK2α1 and/or CK2α2) and two regulatory subunits (CK2β). CK2α1 is a drug target for nephritis and cancers, while CK2α2 is a serious off-target because its inhibition causes testicular toxicity. High similarity between the isozymes CK2α1 and CK2α2 make it difficult to design CK2α1-specific inhibitors. Herein, the crystal structures of CK2α1 and CK2α2 complexed with a 3-amino-pyrazole inhibitor revealed the remarkable differences in the protein-inhibitor interaction modes. This inhibitor bound to the ATP binding sites of both isozymes in apparently distinct orientations. In addition, another molecule of this inhibitor bound to CK2α1, but not to CK2α2, at the CK2β protein-protein interface. Binding energy calculations and biochemical experiments suggested that this inhibitor possesses the conventional ATP-competitive characteristics with moderate allosteric function in a molecular glue mechanism. These results will assist the potential design of potent and selective CK2α1 inhibitors.

PubMed: 36130444
DOI: 10.1016/j.bbrc.2022.09.040

実験手法

X-RAY DIFFRACTION (1.77 Å)