6l24
Crystal structure of CK2a1 H115Y/V116I with hematein
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 catalytic subunit (CK2alpha) is classified into two subtypes CK2alpha1 and CK2alpha2. CK2alpha1 is a drug discovery target, whereas CK2alpha2 is an off-target of CK2alpha1 inhibitors. High amino acid sequence homology between these subtypes hampers efforts to produce ATP competitive inhibitors that are highly selective to CK2alpha1. Hematein was identified previously as a non-ATP-competitive inhibitor for CK2alpha1, whereas this compound acts as an ATP competitive CK2alpha2 inhibitor. Crystal structures of CK2alpha1 and CK2alpha2 in complex with hematein revealed distinct binding features that provide structural insights for producing CK2alpha1-selective inhibitors. Structural insights for producing CK2alpha1-specific inhibitors.,Tsuyuguchi M, Nakaniwa T, Hirasawa A, Nakanishi I, Kinoshita T Bioorg Med Chem Lett. 2020 Jan 15;30(2):126837. doi: 10.1016/j.bmcl.2019.126837. , Epub 2019 Dec 3. PMID:31859160[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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