2vag | pdb_00002vag

Crystal structure of di-phosphorylated human CLK1 in complex with a novel substituted indole inhibitor

spinqualitylabelsall models 2vag, resolution 1.80Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 2vag is a 1 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 1.8Å Ligands: SEP, TPO, V25 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function CLK1_HUMAN Dual specificity kinase acting on both serine/threonine and tyrosine-containing substrates. Phosphorylates serine- and arginine-rich (SR) proteins of the spliceosomal complex and may be a constituent of a network of regulatory mechanisms that enable SR proteins to control RNA splicing. Phosphorylates: SRSF1, SRSF3 and PTPN1. Regulates the alternative splicing of tissue factor (F3) pre-mRNA in endothelial cells and adenovirus E1A pre-mRNA. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed There is a growing recognition of the importance of protein kinases in the control of alternative splicing. To define the underlying regulatory mechanisms, highly selective inhibitors are needed. Here, we report the discovery and characterization of the dichloroindolyl enaminonitrile KH-CB19, a potent and highly specific inhibitor of the CDC2-like kinase isoforms 1 and 4 (CLK1/CLK4). Cocrystal structures of KH-CB19 with CLK1 and CLK3 revealed a non-ATP mimetic binding mode, conformational changes in helix alphaC and the phosphate binding loop and halogen bonding to the kinase hinge region. KH-CB19 effectively suppressed phosphorylation of SR (serine/arginine) proteins in cells, consistent with its expected mechanism of action. Chemical inhibition of CLK1/CLK4 generated a unique pattern of splicing factor dephosphorylation and had at low nM concentration a profound effect on splicing of the two tissue factor isoforms flTF (full-length TF) and asHTF (alternatively spliced human TF). Specific CLK inhibitors from a novel chemotype for regulation of alternative splicing.,Fedorov O, Huber K, Eisenreich A, Filippakopoulos P, King O, Bullock AN, Szklarczyk D, Jensen LJ, Fabbro D, Trappe J, Rauch U, Bracher F, Knapp S Chem Biol. 2011 Jan 28;18(1):67-76. PMID:21276940 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Dual specificity protein kinase 3D structures

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