title: FGF binding and FGF receptor activation by synthetic heparan-derived di- and trisaccharides.
abstract: Fibroblast growth factors (FGFs) require a polysaccharide cofactor, heparin or heparan sulfate (HS), for receptor binding and activation. To probe the molecular mechanism by which heparin or HS (heparin/HS) activates FGF, small nonsulfated oligosaccharides found within heparin/HS were assayed for activity. These synthetic and isomerically pure compounds can activate the FGF signaling pathway. The crystal structures of complexes between FGF and these heparin/HS oligosaccharides reveal several binding sites on FGF and constrain possible mechanisms by which heparin/HS can activate the FGF receptor. These studies establish a framework for the molecular design of compounds capable of modulating FGF activity.
authors.affiliation: Department of Molecular Biology and Pharmacology, Washington University Medical School, St. Louis, MO 63110, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Ornitz
authors.forename: A B
authors.initials: AB
authors.lastname: Herr
authors.forename: M
authors.initials: M
authors.lastname: Nilsson
authors.forename: J
authors.initials: J
authors.lastname: Westman
authors.forename: C M
authors.initials: CM
authors.lastname: Svahn
authors.forename: G
authors.initials: G
authors.lastname: Waksman
mesh_terms: D000818:Animals; D001665:Binding Sites; D002240:Carbohydrate Sequence; D002460:Cell Line; D003460:Crystallization; D016220:Fibroblast Growth Factor 1 / Q000737:chemistry / Q000378:metabolism*; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D006493:Heparin / Q000378:metabolism / Q000494:pharmacology*; D006497:Heparan Sulfate / Q000737:chemistry / Q000494:pharmacology*; D008934:Mitogens / Q000494:pharmacology; D008969:Molecular Sequence Data; D009844:Oligosaccharides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D016220:Fibroblast Growth Factor 1; D016222:Fibroblast Growth Factor 2; D006493:Heparin; D006497:Heparan Sulfate; D008934:Mitogens; D009844:Oligosaccharides; D017468:Receptors, Fibroblast Growth Factor; D011993:Recombinant Fusion Proteins