9r5c
Crystal structure of human protein kinase CK2 catalytic subunit (isoenzyme ck2alpha'; CSNK2A2 gene product) in complex with 4,7-dibromo-5,6-difluoro-1H-1,2,3-benzotriazole
Structural highlights
FunctionCSK22_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] Publication Abstract from PubMedIncorporating fluorine into ligand structures is one of the most common and widely used modifications in modern drug design and pharmacology. Substitution with this small electronegative atom alters physicochemical and pharmacological properties, including standard ADME (Absorption, Distribution, Metabolism, and Excretion) parameters, thereby modulating the activity. In this analysis, we explore these effects using a well-studied model of the catalytic domain of human protein kinase CK2 (hCK2alpha) and halogenated derivatives of 1-H-benzotriazole (Bt). Replacing hydrogen atoms with fluorine alters ligands' inhibitory activity and physicochemical properties, making some more suitable for therapeutic applications. Among the compounds analyzed, 5,6-dibromo-4,7-difluoro-1H-benzotriazole (FBBF) was identified as a promising lead for the further development of CK2 inhibitors. Novel fluoro-brominated benzotriazoles as potential CK2 inhibitors. How does fluorination affect the properties of benzotriazoles?,Kasperowicz S, Werner C, Podsiadla-Bialoskorska M, Szolajska E, Maciejewska AM, Lindenblatt D, Niefind K, Poznanski J, Winiewska-Szajewska M Bioorg Chem. 2025 Dec 26;169:109446. doi: 10.1016/j.bioorg.2025.109446. PMID:41461124[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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