Plotnikov A N, Hubbard S R, Schlessinger J, Mohammadi M
Department of Pharmacology, New York University School of Medicine, New York 10016, USA.
Cell. 2000 May 12;101(4):413-24. doi: 10.1016/s0092-8674(00)80851-x.
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.
为了阐明成纤维细胞生长因子（FGF）信号传导中决定特异性的结构因素，我们分别测定了FGF1和FGF2与成纤维细胞生长因子受体1（FGFR1）和成纤维细胞生长因子受体2（FGFR2）的配体结合结构域（免疫球蛋白样结构域2 [D2]和3 [D3]）形成复合物的晶体结构。高度保守的FGF-D2和FGF-连接子（D2-D3之间）界面定义了所有FGF-FGFR复合物的通用结合位点。特异性是通过FGFs的N端和中央区域与D3中两个可变剪接的环区域之间的相互作用实现的。这些结构为FGF1作为通用FGFR配体以及通过一级序列变异和可变剪接调节FGF-FGFR特异性提供了分子基础。
