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人类副甲状腺激素受体-1 的结构和动态

Li-Hua Zhao¹, Shanshan Ma^1,2, Ieva Sutkeviciute³

¹The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.

Science (New York, N.Y.)

|April 13, 2019

概括

我们确定了附甲状腺激素受体-1 (PTH1R) 与PTH类似物和G蛋白结合的冷EM结构. 这揭示了PTH1R激活如何涉及跨膜螺旋6和动态细胞外域构造.

科学领域:

生物化学
结构生物学
药理学

背景情况:

甲状腺激素受体-1 (PTH1R) 是B类G蛋白合受体,对平衡至关重要.
PTH1R是骨质疏松症和副甲状腺症等疾病的关键治疗点.

研究的目的:

阐明长效PTH类似物激活PTH1R的结构机制.
为了可视化 PTH1R 结合体和刺激性 G 蛋白之间的相互作用.

主要方法:

使用冷电子显微镜 (cryo-EM) 来确定高分辨率的结构.
人类PTH1R与PTH模拟物和G蛋白复合的结构得到了解决.

主要成果:

PTH模拟器的N端插入受体的跨膜域 (TMD),导致部分解和跨膜螺旋6的扭曲.
这种结构重组促进了G蛋白的合.
受体的细胞外域表现出多种构造,表明动态的结构状态.

结论:

这项研究为PTH1R激活的结构基础提供了原子层面的见解.
了解这些动态对于设计针对PTH1R治疗骨疾病和代谢障碍的新疗法至关重要.

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