5okt

Crystal structure of human Casein Kinase I delta in complex with IWP-2

spinqualitylabelsall models 5okt, resolution 2.13Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5okt is a 4 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 2.13Å Ligands: 9XK, ACT, GOL, SO4, TPO 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 Inhibitors of Wnt Production (IWPs) are known antagonists of the Wnt pathway, targeting the membrane-bound O-acyltransferase Porcupine (Porcn) and thus preventing a crucial Wnt ligand palmitoylation. Since IWPs show structural similarities to benzimidazole-based CK1 inhibitors, we hypothesized that IWPs could also inhibit CK1 isoforms. Molecular modeling revealed a plausible binding mode of IWP-2 in the ATP binding pocket of CK1 which was confirmed by X-ray analysis. In vitro kinase assays demonstrated IWPs to be ATP-competitive inhibitors of wtCK1delta. IWPs also strongly inhibited the gatekeeper mutant M82FCK1delta. When profiled in a panel of 320 kinases IWP-2 specifically inhibited CK1delta. IWP-2 and IWP-4 also inhibited the viability of various cancer cell lines. By a medicinal chemistry approach, we developed improved IWP-derived CK1 inhibitors. Our results suggest that the effects of IWPs are not limited to Porcn, but also might influence CK1delta/epsilon-related pathways. Discovery of Inhibitor of Wnt Production 2 (IWP-2) and related compounds as selective ATP-competitive inhibitors of Casein Kinase 1 (CK1) delta/epsilon.,Garcia-Reyes B, Witt L, Jansen B, Karasu E, Gehring T, Leban J, Henne-Bruns D, Pichlo C, Brunstein E, Baumann U, Wesseler F, Rathmer B, Schade D, Peifer C, Knippschild U J Med Chem. 2018 Apr 9. doi: 10.1021/acs.jmedchem.8b00095. PMID:29630366 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Casein kinase 3D structures

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