6jpj | pdb_00006jpj

Crystal structure of FGF401 in complex of FGFR4

spinqualitylabelsall models 6jpj, resolution 2.64Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6jpj is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: FGF, SO4 Gene: FGFR4, JTK2, TKF (HUMAN) Activity: Receptor protein-tyrosine kinase, with EC number 2.7.10.1 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [FGFR4_HUMAN] Tyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors and plays a role in the regulation of cell proliferation, differentiation and migration, and in regulation of lipid metabolism, bile acid biosynthesis, glucose uptake, vitamin D metabolism and phosphate homeostasis. Required for normal down-regulation of the expression of CYP7A1, the rate-limiting enzyme in bile acid synthesis, in response to FGF19. Phosphorylates PLCG1 and FRS2. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Promotes SRC-dependent phosphorylation of the matrix protease MMP14 and its lysosomal degradation. FGFR4 signaling is down-regulated by receptor internalization and degradation; MMP14 promotes internalization and degradation of FGFR4. Mutations that lead to constitutive kinase activation or impair normal FGFR4 inactivation lead to aberrant signaling. Publication Abstract from PubMed Biochemical and structural studies provide information on the mode of action of FGF401 as a selective, reversible covalent inhibitor of FGFR4. Kinase and proliferation assays reveal that FGF401 has the ability to overcome gatekeeper mutations in FGFR4. Characterization of FGF401 as a reversible covalent inhibitor of fibroblast growth factor receptor 4.,Zhou Z, Chen X, Fu Y, Zhang Y, Dai S, Li J, Chen L, Xu G, Chen Z, Chen Y Chem Commun (Camb). 2019 May 1. doi: 10.1039/c9cc02052g. PMID:31041948 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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