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

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 activity^3,4,5. Although crystal structures of binary complexes of FGF–heparin^6,7 and FGF–FGFR^8,9 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.