Molecular mechanism of inhibition of nonclassical FGF-1 export.
Molecular mechanism of inhibition of nonclassical FGF-1 export.
复制标题
抑制非经典 FGF-1 输出的分子机制。
DOI：
10.1021/bi0516071
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发表时间：
2005
期刊：
影响因子：
--
通讯作者：
Yu,Chin
中科院分区：
文献类型：
--
作者：
Rajalingam,Dakshinamurthy;Kumar,ThallapuranamKrishnaswamyS;Soldi,Raffaella;Graziani,Irene;Prudovsky,Igor;Yu,Chin
成纤维细胞生长因子 (FGF-1) 缺乏信号序列，通过非常规释放机制输出。 FGF-1 的非经典输出已被证明可被抗过敏和抗炎药物 amlexanox (AMX) 抑制。我们使用包括多维核磁共振波谱在内的多种生物物理技术，研究了 AMX 对 FGF-1 释放抑制作用的分子机制。 AMX 与 FGF-1 结合并增强其构象稳定性。 AMX 与 Cys30 附近的位置结合，并在空间上阻断 Cu2+ 诱导的氧化，导致 FGF-1 同二聚体的形成。在无细胞条件和活细胞中均观察到 AMX 诱导的 FGF-1 同二聚体形成抑制。这项研究的结果提出了一种设计针对 FGF-1 介导的疾病的药物的新方法。
Fibroblast growth factor (FGF-1) lacks a signal sequence and is exported by an unconventional release mechanism. The nonclassical export of FGF-1 has been shown to be inhibited by an anti-allergic and anti-inflammatory drug, amlexanox (AMX). We investigate the molecular mechanism(s) underlying the inhibitory action of AMX on the release of FGF-1, using a variety of biophysical techniques including multidimensional NMR spectroscopy. AMX binds to FGF-1 and enhances its conformational stability. AMX binds to locations close to Cys30 and sterically blocks Cu2+-induced oxidation, leading to the formation of the homodimer of FGF-1. AMX-induced inhibition of the formation of the FGF-1 homodimer is observed both under cell-free conditions and in living cells. Results of this study suggest a novel approach for the design of drugs against FGF-1-mediated disorders.