在FGF23信号传输中的结构不对称性
Shih-Hsien Liu1, Zhousheng Xiao2, Jeremy C Smith1
1UT/ORNL Center for Molecular Biophysics, Oak Ridge National Laboratory, Oak Ridge, TN 37831, USA; Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee, Knoxville, TN 37996, USA.
Trends in pharmacological sciences
|October 1, 2023
概括
研究人员使用冷EM可视化了纤维细胞生长因子23 (FGF23) 信号复合体. 不对称的结构揭示了FGF23的新见解.
科学领域:
- 结构生物学 结构生物学
- 内分泌学 在内分泌学.
- 生物化学 生化学
背景情况:
- 纤维细胞生长因子23 (FGF23) 是一个关键的内分泌激素,调节酸盐和维生素D代谢.
- FGF23信号的失调与各种疾病有关,包括脏疾病和瘤结症.
- 了解FGF23的分子相互作用对于治疗干预至关重要.
研究的目的:
- 为了确定FGF23信号复合体的高分辨率结构.
- 阐明FGF23受体激活背后的分子机制.
- 为开发针对FGF23信号的新疗法提供结构基础.
主要方法:
- 低温电子显微镜 (cryo-EM) 被用来解决这些结构.
- 使用了FGF23,FGFR,α-Klotho和肝素硫酸盐的净化重组蛋白.
- 进行了计算建模和结构分析.
主要成果:
- 确定了FGF23-FGFR-α-Klotho-heparin硫酸盐信号复合物的不对称结构.
- 确定了关键的相互作用接口和构造状态.
- 结构异质性表明复杂形成的动态方面.
结论:
- 衍生出的冷电磁结构为FGF23信号机器提供了前所未有的原子级细节.
- 观察到的不对称性引发了关于体内功能机制的重要问题.
- 这些发现将促进基于结构的药物设计,以调节FGF23信号通路.
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