5mqv

Crystal structure of human Casein Kinase I delta in complex with 4-(2,5-Dimethoxyphenyl)-N-(4-(5-(4-fluorphenyl)-2-(methylthio)-1H-imidazol-4-yl)-pyridin-2-yl)-1-methyl-1H-pyrrole-2-carboxamide

spinqualitylabelsall models 5mqv, resolution 2.15Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5mqv is a 6 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.154Å Ligands: D5Q, PO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease KC1D_HUMAN Familial advanced sleep-phase syndrome. The disease is caused by mutations affecting the gene represented in this entry. Function KC1D_HUMAN Essential serine/threonine-protein kinase that regulates diverse cellular growth and survival processes including Wnt signaling, DNA repair and circadian rhythms. It can phosphorylate a large number of proteins. Casein kinases are operationally defined by their preferential utilization of acidic proteins such as caseins as substrates. Phosphorylates connexin-43/GJA1, MAP1A, SNAPIN, MAPT/TAU, TOP2A, DCK, HIF1A, EIF6, p53/TP53, DVL2, DVL3, ESR1, AIB1/NCOA3, DNMT1, PKD2, YAP1, PER1 and PER2. Central component of the circadian clock. May act as a negative regulator of circadian rhythmicity by phosphorylating PER1 and PER2, leading to retain PER1 in the cytoplasm. YAP1 phosphorylation promotes its SCF(beta-TRCP) E3 ubiquitin ligase-mediated ubiquitination and subsequent degradation. DNMT1 phosphorylation reduces its DNA-binding activity. Phosphorylation of ESR1 and AIB1/NCOA3 stimulates their activity and coactivation. Phosphorylation of DVL2 and DVL3 regulates WNT3A signaling pathway that controls neurite outgrowth. EIF6 phosphorylation promotes its nuclear export. Triggers down-regulation of dopamine receptors in the forebrain. Activates DCK in vitro by phosphorylation. TOP2A phosphorylation favors DNA cleavable complex formation. May regulate the formation of the mitotic spindle apparatus in extravillous trophoblast. Modulates connexin-43/GJA1 gap junction assembly by phosphorylation. Probably involved in lymphocyte physiology. Regulates fast synaptic transmission mediated by glutamate. Publication Abstract from PubMed The involvement of protein kinase CK1delta in the pathogenesis of severe disorders such as Alzheimer's disease, amyotrophic lateral sclerosis, familial advanced sleep phase syndrome, and cancer has dramatically increased interest in the development of effective small molecule inhibitors for both therapeutic application and basic research. Unfortunately, the design of CK1 isoform-specific compounds has proved to be highly complicated due to the existence of six evolutionarily conserved human CK1 members that possess similar, different, or even opposite physiological and pathophysiological implications. Consequently, only few potent and selective CK1delta inhibitors have been reported so far and structurally divergent approaches are urgently needed in order to establish SAR that might enable complete discrimination of CK1 isoforms and related p38alpha MAPK. In this study we report on design and characterization of optimized 4,5-diarylimidazoles as highly effective ATP-competitive inhibitors of CK1delta with compounds 11b (IC50 CK1delta = 4 nM, IC50 CK1epsilon = 25 nM), 12a (IC50 CK1delta = 19 nM, IC50 CK1epsilon = 227 nM), and 16b (IC50 CK1delta = 8 nM, IC50 CK1epsilon = 81 nM) being among the most potent CK1delta-targeting agents published to date. Inhibitor compound 11b, displaying potential as a pharmacological tool, has further been profiled over a panel of 321 protein kinases exhibiting high selectivity. Cellular efficacy has been evaluated in human pancreatic cancer cell lines Colo357 (EC50 = 3.5 microM) and Panc89 (EC50 = 1.5 microM). SAR is substantiated by X-ray crystallographic analysis of 16b in CK1delta and 11b in p38alpha. Optimized 4,5-Diarylimidazoles as Potent/Selective Inhibitors of Protein Kinase CK1delta and Their Structural Relation to p38alpha MAPK.,Halekotte J, Witt L, Ianes C, Kruger M, Buhrmann M, Rauh D, Pichlo C, Brunstein E, Luxenburger A, Baumann U, Knippschild U, Bischof J, Peifer C Molecules. 2017 Mar 24;22(4). pii: E522. doi: 10.3390/molecules22040522. PMID:28338621 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Casein kinase 3D structures

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