Figure 7. Ligand-dependent differences at the FGF–FGFR interface differentially regulate FGFR dimerization.

a | Superimposition of a 2:2 fibroblast growth factor 8b–FGF receptor 2c (FGF8b–FGFR2c) complex onto a 2:2 FGF2 – FGFR2c complex. The α-carbon traces of the complexes are shown. For the FGF8b–FGFR2c complex model, FGF8b from the FGF8b–FGFR2c structure (Protein Databank identifier (PDB ID): 2FDB)³⁷ was superimposed onto each of the two FGF2 ligands in the 2:2:2 FGF2–FGFR1c–heparan sulphate complex (PDB ID: 1FQ9)⁴. The FGF2–FGFR2c model was created in a similar manner using FGF2 from the FGF2–FGFR2c structure (PDB ID: 1EV2)⁸². Note the differences in the orientation of the receptor D3 domain and D2–D3 linker between the two dimers of ligand-bound FGFR2c, which translate into differences in the spatial distance between the carboxy-terminal membrane insertion points of the D3 domains.b | The interface between the ligand and the D3 domain and D2–D3 linker of the receptor in the FGF2–FGFR2c structure (PDB ID: 1EV2)⁸² is shown. The ligand is coloured orange, the receptor is coloured green (D2–D3 linker and common amino-terminal portion of the D3 domain) and teal (alternatively spliced C-terminal portion of the D3 domain). The network of hydrogen bonds (dashed lines) formed at this interface is highly conserved among complexes of FGFR with FGF1 subfamily ligands or FGF10. Its key constituents comprise Glu105 and Asn113 of FGF2 and Arg251, Asp283 and Gln285 of FGFR2c. Most of these residues also form entropically favourable intramolecular hydrogen bonds with similarly conserved residues, such as Glu105 and Asn113 of FGF2 with Tyr115 of FGF2.c | The interface between the ligand and the D3 domain and D2–D3 linker of the receptor in the FGF8b–FGFR2c structure (PDB ID: 2FDB)³⁷ is shown. Ligand and receptor are coloured as in partb. The composition and geometry of the network of hydrogen bonds (dashed lines) formed at this interface differ from that observed in the FGF2–FGFR2c complex (see, partb). For example, Asn113 and Tyr115 of FGF2 are replaced with Thr and Leu, respectively, in FGF8b. The side chain of Glu131 in FGF8b, the corresponding residue to Glu105 in FGF2, adopts a different rotamer conformation compared to that in the FGF2–FGFR2c complex as it makes an intramolecular hydrogen bond with Lys176, a residue specific to FGF8 subfamily ligands. A total of four hydrogen bonds unique to the FGF8b–FGFR2c complex (dashed red lines) are formed at this interface between FGF8b and FGFR2c. Images in partsb and c are modified, with permission, from REF. 37 © (2006) Cold Spring Harbor Laboratory Press.