title: Structural analysis of the human fibroblast growth factor receptor 4 kinase.
abstract: The family of fibroblast growth factor receptors (FGFRs) plays an important and well-characterized role in a variety of pathological disorders. FGFR4 is involved in myogenesis and muscle regeneration. Mutations affecting the kinase domain of FGFR4 may cause cancer, for example, breast cancer or rhabdomyosarcoma. Whereas FGFR1-FGFR3 have been structurally characterized, the structure of the FGFR4 kinase domain has not yet been reported. In this study, we present four structures of the kinase domain of FGFR4, in its apo-form and in complex with different types of small-molecule inhibitors. The two apo-FGFR4 kinase domain structures show an activation segment similar in conformation to an autoinhibitory segment observed in the hepatocyte growth factor receptor kinase but different from the known structures of other FGFR kinases. The structures of FGFR4 in complex with the type I inhibitor Dovitinib and the type II inhibitor Ponatinib reveal the molecular interactions with different types of kinase inhibitors and may assist in the design and development of FGFR4 inhibitors.
authors.affiliation: Max Planck Institut für Biochemie, Am Klopferspitz 18, D-82152 Martinsried, Germany; Proteros Biostructures GmbH, Bunsenstraße 7a, D-82152 Martinsried, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Lesca
authors.affiliation: Proteros Biostructures GmbH, Bunsenstraße 7a, D-82152 Martinsried, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Lammens
authors.affiliation: Max Planck Institut für Biochemie, Am Klopferspitz 18, D-82152 Martinsried, Germany; Zentrum für Medizinische Biotechnologie, Universität Duisburg-Essen, D-45117 Essen, Germany; School of Biosciences, Cardiff University, Cardiff CF10 3US, UK; Fakultät für Chemie, Technische Universität München, Lichtenbergstraße 4, D-85747 Garching, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Huber
authors.affiliation: Proteros Biostructures GmbH, Bunsenstraße 7a, D-82152 Martinsried, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Augustin
mesh_terms: D001051:Apoenzymes; D001562:Benzimidazoles / Q000737:chemistry* / Q000378:metabolism; D015153:Blotting, Western; D018360:Crystallography, X-Ray; D006801:Humans; D007093:Imidazoles / Q000737:chemistry* / Q000378:metabolism; D010766:Phosphorylation; D011487:Protein Conformation; D011724:Pyridazines / Q000737:chemistry* / Q000378:metabolism; D015363:Quinolones / Q000737:chemistry* / Q000378:metabolism; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000737:chemistry* / Q000378:metabolism
chemical_list: C500007:4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one; D001051:Apoenzymes; D001562:Benzimidazoles; D007093:Imidazoles; D011724:Pyridazines; D015363:Quinolones; C545373:ponatinib; C496371:FGFR4 protein, human; D051499:Receptor, Fibroblast Growth Factor, Type 4
keywords: Dovitinib; Ponatinib; autoinhibition; rhabdomyosarcoma; tyrosine receptor kinase