7XYH

Crystal structure of CK2a2 complexed with AG1112

Summary for 7XYH

• Entry DOI: 10.2210/pdb7xyh/pdb
• Descriptor: Casein kinase II subunit alpha', 5-azanyl-3-[(~{Z})-1-cyano-2-(1~{H}-indol-3-yl)ethenyl]-1~{H}-pyrazole-4-carbonitrile, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: protein kinase, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 81613.34

Authors

Ikeda, A.,Kinoshita, T.,Tsuyuguchi, M. (deposition date: 2022-06-01, release date: 2023-01-18, Last modification date: 2023-11-29)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.04 Å)