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

被引:592
作者
Pellegrini, L
Burke, DF
von Delft, F
Mulloy, B
Blundell, TL
机构
[1] Univ Cambridge, Dept Biochem, Cambridge CB2 1GA, England
[2] Natl Inst Biol Stand & Controls, Potters Bar EN6 3QG, Herts, England
关键词
D O I
10.1038/35039551
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Fibroblast growth factors (FGFs) are a large family of structurally related proteins with a wide range of physiological and pathological activities(1). 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(3-5). 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.
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页码:1029 / 1034
页数:7
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