Crystal structures of two FGF-FGFR complexes reveal the determinants of ligand-receptor specificity

To elucidate the structural determinants governing specificity in fibroblas t 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, respec tively. Highly conserved FGF-D2 and FGF-linker (between D2-D3) interfaces d efine a general binding site for all FGF-FGFR complexes. Specificity is ach ieved through interactions between the N-terminal and central regions of FG Fs and two loop regions in D3 that are subject to alternative splicing. The se structures provide a molecular basis for FGF1 as a universal FGFR ligand and for modulation of FGF-FGFR specificity through primary sequence variat ions and alternative splicing.