6gih
From Proteopedia
Crystal Structure of CK2alpha with CAM187 bound
Structural highlights
Function[CSK21_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 PubMedIncreased CK2 levels are prevalent in many cancers. Combined with the critical role CK2 plays in many cell-signaling pathways, this makes it a prime target for down regulation to fight tumour growth. Herein, we report a fragment-based approach to inhibiting the interaction between CK2alpha and CK2beta at the alpha-beta interface of the holoenzyme. A fragment, CAM187, with an IC50 of 44muM and a molecular weight of only 257gmol(-1) has been identified as the most promising compound. Importantly, the lead fragment only bound at the interface and was not observed in the ATP binding site of the protein when co-crystallised with CK2alpha. The fragment-like molecules discovered in this study represent unique scaffolds to CK2 inhibition and leave room for further optimisation. Novel non-ATP competitive small molecules targeting the CK2 alpha/beta interface.,Brear P, North A, Iegre J, Hadje Georgiou K, Lubin A, Carro L, Green W, Sore HF, Hyvonen M, Spring DR Bioorg Med Chem. 2018 May 9. pii: S0968-0896(18)30329-8. doi:, 10.1016/j.bmc.2018.05.011. PMID:29759799[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. Loading citation details.. Citations No citations found References
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Categories: Human | Non-specific serine/threonine protein kinase | Brear, P | Carro, L | Fusco, C De | Georgiou, K | Hyvonen, M | Iegre, J | Lubin, A | North, A | Sore, H | Spring, D | Ck2a | Ck2alpha | Fragment based drug discovery | High concentration screening | Selective atp competitive inhibitor | Surface entrophy reduction | Transferase
