脊柱修饰的葡萄糖样-1类似物与多种受体贩运的长时间信号传递
Brian P Cary1,2,3, Marlies V Hager1, Zamara Mariam4
1Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706.
概括
新的葡萄糖类-1受体 (GLP-1R) 类似物显示出延长的信号持续时间. 修改影响受体内细胞结核和结构,提供了对G蛋白结合受体 (GPCR) 激活动态的见解.
科学领域:
- 生物化学 生物化学
- 分子药理学分子药理学
- 结构生物学 结构生物学
背景情况:
- 通过信号持续时间和亚细胞局部化,越来越多地了解G蛋白结合受体 (GPCR) 功能.
- 葡萄糖类-1受体 (GLP-1R) 是糖尿病治疗的关键标,通过循环腺单酸盐 (cAMP) 生产调解细胞反应.
- 持续的cAMP信号传递甚至发生在GLP-1R通过内细胞化内部化后.
研究的目的:
- 与原生GLP-1相比,开发具有延长信号持续时间的GLP-1类似物.
- 研究特定氨基酸替代对GLP-1R信号传递,内细胞和受体结合结构的影响.
- 阐明GLP-1R激活中改变信号配置的结构基础.
主要方法:
- 设计和合成包含β-氨基酸 (ACPC和Aib) 的修改GLP-1类型.
- 评估GLP-1R信号持续时间和受体内细胞分裂.
- 低温电子显微镜 (Cryo-EM) 用于确定GLP-1R-agonist复合物的结构.
主要成果:
- 在位置18 (ACPC) 进行单次β-氨基酸替代,延长了GLP-1R信号传递,同时保持了内细胞分裂.
- 双替代 (Aib在位置16和ACPC在位置18) 废除了内细胞形成,但保持了长时间的信号传递.
- 与原生GLP-1相比,冷EM结构显示了同类的结合形状和动态的显著变化.
- 长时间的信号有效性取决于在位置18的特定β-残留结构.
结论:
- 修改的GLP-1类似物可以通过不同的机制实现长时间的信号传递,包括改变的内细胞形成或构造变化.
- 受体结合状态内的激素诱导的结构动态是信号持续时间的关键决定因素.
- 这些发现为剖析GLP-1R信号传递和受体激活的时空方面提供了新的工具.
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