Crystal structures of two FGF-FGFR complexes reveal the determinants of ligand-receptor specificity.
To elucidate the structural determinants governing specificity in fibroblast growth factor (FGF) signaling, we have determined the crystal structures of FGF1 and FGF2 complexed with the ligand binding domains (immunoglobulin-like domains 2 [D2] and 3 [D3]) of FGF receptor 1 (FGFR1) and FGFR2, respectively. Highly conserved FGF-D2 and FGF-linker (between D2-D3) interfaces define a general binding site for all FGF-FGFR complexes. Specificity is achieved through interactions between the N-terminal and central regions of FGFs and two loop regions in D3 that are subject to alternative splicing. These structures provide a molecular basis for FGF1 as a universal FGFR ligand and for modulation of FGF-FGFR specificity through primary sequence variations and alternative splicing.
Plotnikov
A N
AN
Department of Pharmacology, New York University School of Medicine, New York 10016, USA.
Hubbard
S R
SR
Schlessinger
J
J
Mohammadi
M
M
D000595:Amino Acid Sequence; D016220:Fibroblast Growth Factor 1; D016222:Fibroblast Growth Factor 2 / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D017468:Receptors, Fibroblast Growth Factor / Q000737:chemistry*; D015398:Signal Transduction
D008024:Ligands; D017468:Receptors, Fibroblast Growth Factor; D016222:Fibroblast Growth Factor 2; D016220:Fibroblast Growth Factor 1