The Crystal Structure of Fibroblast Growth Factor (FGF) 19 Reveals Novel Features of the FGF Family and Offers a Structural Basis for Its Unusual Receptor Affinity^,

Abstract

The 22 members of the FGF family have been implicated in cell proliferation, differentiation, survival, and migration. They are required for both development and maintenance of vertebrates, demonstrating an exquisite pattern of affinities for both protein and proteoglycan receptors. FGF19, one of the most divergent human FGFs, is unique in binding solely to one receptor, FGFR4. We have used molecular replacement to solve the crystal structure of FGF19 at 1.3 Å resolution using five superimposed FGF structures as the search model. The structure shows that two novel disulfide bonds found in FGF19, one of which appears to be conserved among several of the other FGFs, stabilize extended loops. The key heparin-binding loops of FGF19 have radically different conformations and charge patterns, compared to other FGFs, correlating with the unusually low affinity of FGF19 for heparin. A model for the complex of FGF19 with FGFR4 demonstrates that unique sequences in both FGF19 and FGFR4 are key to the formation of the complex. The structure therefore offers a clear explanation for the unusual affinity of FGF19 for FGFR4 alone.

Combination of the FGFR4 inhibitor PD173074 and 5-fluorouracil reduces proliferation and promotes apoptosis in gastric cancer

“…Among more than 20 FGF ligands, only FGF19 can directly and specifically combine to FGFR4 (13,14). Moreover, no matter whether β-Klotho was present, FGF19 led to biological effects by combining with FGFR4 (15).…”

FGFR4 Prevents Hyperlipidemia and Insulin Resistance but Underlies High-Fat Diet–Induced Fatty Liver

“…It has also been reported that mice with an FGFR4 gene deletion are still metabolically responsive to systemic FGF19 (13). Although it has been argued that FGF19 may be a specific FGF ligand for FGFR4 (48,49), this specificity has yet to be confirmed, particularly in tissues where FGFR4 has impact. Another candidate FGF ligand for FGFR4 particularly in hepatocytes is FGF21.…”

1.15 Å Crystal structure of the X. tropicalis Spred1 EVH1 domain suggests a fourth distinct peptide‐binding mechanism within the EVH1 family

“…Data were collected to 1.15 Å at the Daresbury Synchrotron Radiation Source, station PX14.2, at 100 K. X-ray data were indexed and scaled using the HKL package [13]. To provide phases, structures of Enabled and Homer (PDB codes 1EVH, 1I7A, and 1QC6) were superimposed and altered as described [14] for use as a search model for AMORE [15], searching for two molecules in the asymmetric unit. This provided a solution that gave sufficiently good phases for model building.…”