1. Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge , CB2 1GA, UK
2. National Institute for Biological Standards and Control, South Mimms, Potters Bar, EN6 3QG, UK

Correspondence to: Tom L. Blundell¹ Correspondence and requests for materials should be addressed to L.P (e-mail: Email: luca@cryst.bioc.cam.ac.uk) or T.L.B. (e-mail: Email:  tom@cryst.bioc.cam.ac.uk). Coordinates have been deposited in the Protein Data Bank with accession number 1e0o.

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.