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

Nature volume 407, pages 1029–1034 (2000)Cite this article

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.

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Figure 1: The FGF1–FGFR2–heparin complex.
Figure 2: Heparin–protein interactions in the FGF1–FGFR2–heparin complex.
Figure 3: Overall architecture of the FGF1–FGFR2–heparin complex.
Figure 4: Ligand–receptor interactions in FGF–FGFR complexes with and without heparin.
Figure 5: Higher order FGFR oligomerization as observed in crystals of the FGF1–FGFR2–heparin complex.

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Acknowledgements

We would like to thank P. Gadhavi for discussions and early work on FGFR overexpression; D. Chirgadze, E. Parisini and J. Patel for help with X-ray data collection; R. Sanishvili for user support at the SBC beamline; M. Vinkovic for help with the use of SHELX; M. Hyvonen for advice on protein refolding and help with the figures; and M. Symmons for advice on production of selenomethionyl protein. We are grateful to S. Malcolm for insightful comments on the phenotype of FGFR mutations in Apert syndrome and for the FGFR2 cDNA, and to D. Fernig for the FGF1 cDNA. Heparin lyase I was a gift of K. Johansen, Leo Pharmaceuticals, Denmark. This research was supported by grants from the MRC and the Wellcome Trust. Use of the Argonne National Laboratory Structural Biology Center beamlines at the Advanced Photon Source was supported by the US Department of Energy, Basic Energy Sciences, Office of Science.

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  1. Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge , CB2 1GA, UK

    Luca Pellegrini, David F. Burke, Frank von Delft & Tom L. Blundell

  2. National Institute for Biological Standards and Control, South Mimms, Potters Bar, EN6 3QG, UK

    Barbara Mulloy

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  1. Luca Pellegrini
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Correspondence to Tom L. Blundell.

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Pellegrini, L., Burke, D., von Delft, F. et al. Crystal structure of fibroblast growth factor receptor ectodomain bound to ligand and heparin. Nature 407, 1029–1034 (2000). https://doi.org/10.1038/35039551

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