7x4h
Crystal structure of CK2a1 complexed with AG1112
Structural highlights
FunctionCSK21_HUMAN Catalytic subunit of a constitutively active serine/threonine-protein kinase complex that phosphorylates a large number of substrates containing acidic residues C-terminal to the phosphorylated serine or threonine. Regulates numerous cellular processes, such as cell cycle progression, apoptosis and transcription, as well as viral infection. May act as a regulatory node which integrates and coordinates numerous signals leading to an appropriate cellular response. During mitosis, functions as a component of the p53/TP53-dependent spindle assembly checkpoint (SAC) that maintains cyclin-B-CDK1 activity and G2 arrest in response to spindle damage. Also required for p53/TP53-mediated apoptosis, phosphorylating 'Ser-392' of p53/TP53 following UV irradiation. Can also negatively regulate apoptosis. Phosphorylates the caspases CASP9 and CASP2 and the apoptotic regulator NOL3. Phosphorylation protects CASP9 from cleavage and activation by CASP8, and inhibits the dimerization of CASP2 and activation of CASP8. Regulates transcription by direct phosphorylation of RNA polymerases I, II, III and IV. Also phosphorylates and regulates numerous transcription factors including NF-kappa-B, STAT1, CREB1, IRF1, IRF2, ATF1, SRF, MAX, JUN, FOS, MYC and MYB. Phosphorylates Hsp90 and its co-chaperones FKBP4 and CDC37, which is essential for chaperone function. Regulates Wnt signaling by phosphorylating CTNNB1 and the transcription factor LEF1. Acts as an ectokinase that phosphorylates several extracellular proteins. During viral infection, phosphorylates various proteins involved in the viral life cycles of EBV, HSV, HBV, HCV, HIV, CMV and HPV.[1] [2] [3] [4] Publication Abstract from PubMedCasein kinase 2 (CK2) is a vital protein kinase that consists of two catalytic subunits (CK2alpha1 and/or CK2alpha2) and two regulatory subunits (CK2beta). CK2alpha1 is a drug target for nephritis and cancers, while CK2alpha2 is a serious off-target because its inhibition causes testicular toxicity. High similarity between the isozymes CK2alpha1 and CK2alpha2 make it difficult to design CK2alpha1-specific inhibitors. Herein, the crystal structures of CK2alpha1 and CK2alpha2 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 CK2alpha1, but not to CK2alpha2, at the CK2beta 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 CK2alpha1 inhibitors. Bivalent binding mode of an amino-pyrazole inhibitor indicates the potentials for CK2alpha1-selective inhibitors.,Ikeda A, Tsuyuguchi M, Kitagawa D, Sawa M, Nakamura S, Nakanishi I, Kinoshita T Biochem Biophys Res Commun. 2022 Nov 19;630:30-35. doi: , 10.1016/j.bbrc.2022.09.040. Epub 2022 Sep 15. PMID:36130444[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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