4ff8 | pdb_00004ff8
Inhibitor bound structure of the kinase domain of the murine receptor tyrosine kinase TYRO3 (Sky)
Structural highlights
Function[TYRO3_MOUSE] Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding to several ligands including TULP1 or GAS6. Regulates many physiological processes including cell survival, migration and differentiation. Ligand binding at the cell surface induces dimerization and autophosphorylation of TYRO3 on its intracellular domain that provides docking sites for downstream signaling molecules. Following activation by ligand, interacts with PIK3R1 and thereby enhances PI3-kinase activity. Activates the AKT survival pathway, including nuclear translocation of NF-kappa-B and up-regulation of transcription of NF-kappa-B-regulated genes. TYRO3 signaling plays a role in various processes such as neuron protection from excitotoxic injury, platelet aggregation and cytoskeleton reorganization. Plays also an important role in inhibition of Toll-like receptors (TLRs)-mediated innate immune response by activating STAT1, which selectively induces production of suppressors of cytokine signaling SOCS1 and SOCS3.[1] [2] [3] [4] Publication Abstract from PubMedWe report the SAR around a series of 2,4-diaminopyrimidine-5-carboxamide inhibitors of Sky kinase. 2-Aminophenethyl analogs demonstrate excellent potency but moderate kinase selectivity, while 2-aminobenzyl analogs that fill the Ala571 subpocket exhibit good inhibition activity and excellent kinase selectivity. Highly selective 2,4-diaminopyrimidine-5-carboxamide inhibitors of Sky kinase.,Powell NA, Hoffman JK, Ciske FL, Kaufman MD, Kohrt JT, Quin J 3rd, Sheehan DJ, Delaney A, Baxi SM, Catana C, McConnell P, Ohren J, Perrin LA, Edmunds JJ Bioorg Med Chem Lett. 2013 Feb 15;23(4):1046-50. doi: 10.1016/j.bmcl.2012.12.013., Epub 2012 Dec 20. PMID:23312472[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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