Crystal structure of fibroblast growth factor receptor ectodomain bound to ligand and heparin

Luca Pellegrini, David F. Burke, Frank von Delft, Barbara Mulloy and Tom L. Blundell ()
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Luca Pellegrini: University of Cambridge
David F. Burke: University of Cambridge
Frank von Delft: University of Cambridge
Barbara Mulloy: National Institute for Biological Standards and Control, South Mimms
Tom L. Blundell: University of Cambridge

Nature, 2000, vol. 407, issue 6807, 1029-1034

Abstract: Abstract Fibroblast growth factors (FGFs) are a large family of structurally related proteins with a wide range of physiological and pathological activities1. Signal transduction requires association of FGF with its receptor tyrosine kinase (FGFR)2 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 activity3,4,5. Although crystal structures of binary complexes of FGF–heparin6,7 and FGF–FGFR8,9 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.

Date: 2000
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DOI: 10.1038/35039551

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