3rps
Structure of human CK2alpha in complex with the ATP-competitive inhibitor 3-(4,5,6,7-tetrabromo-1H-benzotriazol-1-yl)propan-1-olStructure of human CK2alpha in complex with the ATP-competitive inhibitor 3-(4,5,6,7-tetrabromo-1H-benzotriazol-1-yl)propan-1-ol
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 PubMedEukaryotic protein kinases are fundamental factors for cellular regulation and therefore subject of strict control mechanisms. For full activity a kinase molecule must be penetrated by two stacks of hydrophobic residues, the regulatory and the catalytic spine that are normally well conserved among active protein kinases. We apply this novel spine concept here on CK2alpha, the catalytic subunit of protein kinase CK2. Homo sapiens disposes of two paralog isoforms of CK2alpha (hsCK2alpha and hsCK2alpha'). We describe two new structures of hsCK2alpha constructs one of which in complex with the ATP-analog adenylyl imidodiphosphate and the other with the ATP-competitive inhibitor 3-(4,5,6,7-tetrabromo-1H-benzotriazol-1-yl)propan-1-ol. The former is the first hsCK2alpha structure with a well defined cosubstrate/magnesium complex and the second with an open beta4/beta5-loop. Comparisons of these structures with existing CK2alpha/CK2alpha' and cAMP-dependent protein kinase (PKA) structures reveal: in hsCK2alpha' an open conformation of the interdomain hinge/helix alphaD region that is critical for ATP-binding is found corresponding to an incomplete catalytic spine. In contrast hsCK2alpha often adopts the canonical, PKA-like version of the catalytic spine which correlates with a closed conformation of the hinge region. HsCK2alpha can switch to the incomplete, non-canonical, hsCK2alpha'-like state of the catalytic spine, but this transition apparently depends on binding of either ATP or of the regulatory subunit CK2beta. Thus, ATP looks like an activator of hsCK2alpha rather than a pure cosubstrate. Enzymatic activity with an incomplete catalytic spine: insights from a comparative structural analysis of human CK2alpha and its paralogous isoform CK2alpha'.,Bischoff N, Raaf J, Olsen B, Bretner M, Issinger OG, Niefind K Mol Cell Biochem. 2011 Oct;356(1-2):57-65. Epub 2011 Jul 8. PMID:21739153[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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