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Fibroblast growth factors (FGFs) are a large family of structurally related proteins with a wide range of physiological and pathological activities. Signal transduction requires association of FGF with its receptor tyrosine kinase (FGFR) and heparan sulphate proteoglycan in a specific complex on the cell surface. Direct involvement of the heparan sulphate glycosaminoglycan polysaccharide in the molecular association between FGF and its receptor is essential for biological activity. Although crystal structures of binary complexes of FGF-heparin and FGF-FGFR have been described, the molecular architecture of the FGF signalling complex has not been elucidated. Here we report the crystal structure of the FGFR2 ectodomain in a dimeric form that is induced by simultaneous binding to FGF1 and a heparin decasaccharide. The complex is assembled around a central heparin molecule linking two FGF1 ligands into a dimer that bridges between two receptor chains. The asymmetric heparin binding involves contacts with both FGF1 molecules but only one receptor chain. The structure of the FGF1-FGFR2-heparin ternary complex provides a structural basis for the essential role of heparan sulphate in FGF signalling.

Original publication

DOI

10.1038/35039551

Type

Journal article

Journal

Nature

Publication Date

26/10/2000

Volume

407

Pages

1029 - 1034

Keywords

Amino Acid Sequence, Binding Sites, Crystallography, X-Ray, Escherichia coli, Fibroblast Growth Factor 1, Fibroblast Growth Factor 2, Heparin, Humans, Ligands, Macromolecular Substances, Models, Molecular, Molecular Sequence Data, Protein Binding, Protein Conformation, Protein Structure, Tertiary, Receptor Protein-Tyrosine Kinases, Receptor, Fibroblast Growth Factor, Type 2, Receptors, Fibroblast Growth Factor, Recombinant Proteins