PDBsum entry 1e0o

Growth factor

PDB id: 1e0o

Contents

Protein chains

129 a.a. *

197 a.a. *

Ligands

SGN-IDS-SGN-IDS-SGN-IDS-SGN-IDS-SGN-IDS

SO4 ×5

Metals

_NI ×5

Waters ×41

* Residue conservation analysis

References listed in PDB file

Key reference

Title

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

Authors

L.Pellegrini, D.F.Burke, F.Von delft, B.Mulloy, T.L.Blundell.

Ref.

Nature, 2000, 407, 1029-1034. [DOI no: 10.1038/35039551]

PubMed id

11069186

Abstract

Fibroblast growth factors (FGFs) are a large family of structurally related proteins with a wide range of physiological and pathological activities. Signal transduction requires association of FGF with its receptor tyrosine kinase (FGFR) 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. Although crystal structures of binary complexes of FGF-heparin and FGF-FGFR 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.

Figure 1.
Figure 1: The FGF1-FGFR2-heparin complex. a, View perpendicular to the approximate dyad of the complex. FGFR2 domains 2 (D2) and 3 (D3) are cyan and magenta, respectively, and FGF1 is green. The heparin molecule is in CPK representation. b, View along the dyad. c, Amino-acid sequence of the ligand-binding region of human FGFR2. Domains D2 and D3 are coloured as in a. Residues that interact with heparin and FGF1 are highlighted in red and green, respectively. Regions of secondary structure are boxed. -strands, -helices and 3[ 10] helices are indicated below the relative sequence. D3 residues 294-309, which were disordered in the crystals, are in lower case.

Figure 3.
Figure 3: Overall architecture of the FGF1-FGFR2-heparin complex. a, Electrostatic potential of the heparin-binding site in the FGF1-FGFR2-heparin complex, mapped onto a molecular surface rendition of the complex. The heparin is shown as a stick model. In the ternary complex, the heparin decasaccharide is surrounded by regions of positive charge (blue represents +20e per Å 2). b, Superposition of heparin-linked FGF1 dimers. The dimer from the FGF1-FGFR2-heparin complex is yellow, the PDB entry 2AXM is blue. The FGFR2 ectodomains are shown in CPK representation.

The above figures are reprinted by permission from Macmillan Publishers Ltd: Nature (2000, 407, 1029-1034) copyright 2000.