5x8i

Crystal structure of human CLK1 in complex with compound 25

spinqualitylabelsall models 5x8i, resolution 1.90Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5x8i is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: SQZ Activity: Dual-specificity kinase, with EC number 2.7.12.1 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. Publication Abstract from PubMed Autophagy inducers represent new promising agents for the treatment of a wide range of medical illnesses. However, safe autophagy inducers for clinical applications are lacking. Inhibition of cdc2-like kinase 1 (CLK1) was recently found to efficiently induce autophagy. Unfortunately, most of the known CLK1 inhibitors have unsatisfactory selectivity. Herein, we report the discovery of a series of new CLK1 inhibitors containing the 1H-[1,2,3]triazolo[4,5-c]quinoline scaffold. Among them, compound 25 was the most potent and selective, with an IC50 value of 2 nM against CLK1. The crystal structure of CLK1 complexed with compound 25 was solved, and the potency and kinase selectivity of compound 25 were interpreted. Compound 25 was able to induce autophagy in in vitro assays and displayed significant hepatoprotective effects in the acetaminophen (APAP)-induced liver injury mouse model. Collectively, due to its potency and selectivity, compound 25 could be used as a chemical probe or agent in future mechanism-of-action or autophagy-related disease therapy studies. Discovery of Potent and Selective Inhibitors of Cdc2-Like Kinase 1 (CLK1) as a New Class of Autophagy Inducers.,Sun QZ, Lin GF, Li LL, Jin XT, Huang LY, Zhang G, Yang W, Chen K, Xiang R, Chen C, Wei YQ, Lu GW, Yang SY J Med Chem. 2017 Jul 27;60(14):6337-6352. doi: 10.1021/acs.jmedchem.7b00665. Epub, 2017 Jul 17. PMID:28692292 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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