FGF binding and FGF receptor activation by synthetic heparan-derived di- and trisaccharides.
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.
Ornitz
D M
DM
Department of Molecular Biology and Pharmacology, Washington University Medical School, St. Louis, MO 63110, USA.
Herr
A B
AB
Nilsson
M
M
Westman
J
J
Svahn
C M
CM
Waksman
G
G
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
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