FGF BINDING AND FGF RECEPTOR ACTIVATION BY SYNTHETIC HEPARAN-DERIVED DISACCHARIDES AND TRISACCHARIDES
FGF BINDING AND FGF RECEPTOR ACTIVATION BY SYNTHETIC HEPARAN-DERIVED DISACCHARIDES AND TRISACCHARIDES
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DOI：
10.1126/science.7536345
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发表时间：
1995-04-21
期刊：
影响因子：
56.9
通讯作者：
WAKSMAN, G
中科院分区：
文献类型：
--
作者：
ORNITZ, DM;HERR, AB;WAKSMAN, G
成纤维细胞生长因子（fgf）需要多糖辅助因子肝素或硫酸肝素（HS）来结合和激活受体。为了探究肝素或HS （heparin/HS）激活FGF的分子机制，我们检测了肝素/HS中小的非硫酸低聚糖的活性，这些合成的和异构纯的化合物可以激活FGF信号通路。FGF与这些肝素/HS寡糖之间复合物的晶体结构揭示了FGF上的几个结合位点，并限制了肝素/HS激活FGF受体的可能机制。这些研究为能够调节FGF活性的化合物的分子设计建立了框架。
Fibroblast growth factors (FGFs) require a polysaccharide cofactor, heparin or heparan sulfate (HS), for receptor binding and activation. To probe the molecular mechanism by which heparin or HS (heparin/HS) activates FGF, small nonsulfated oligosaccharides found within heparin/HS were assayed for activity, These synthetic and isomerically pure compounds can activate the FGF signaling pathway. The crystal structures of complexes between FGF and these heparin/HS oligosaccharides reveal several binding sites on FGF and constrain possible mechanisms by which heparin/HS can activate the FGF receptor. These studies establish a framework for the molecular design of compounds capable of modulating FGF activity.