粘附性GPCR的绑定激活的结构基础
Yu-Qi Ping1,2,3,4, Peng Xiao1,5, Fan Yang1,3,5,6
1Key Laboratory Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
Nature
|April 14, 2022
概括
粘附G蛋白合受体 (aGPCRs) 通过绑定的Stachel序列被激活. 化EM结构揭示了这些序列如何结合跨膜域,调解受体激活和Gs合.
科学领域:
- 结构生物学
- 分子生物学
- 生物化学
背景情况:
- 粘附G蛋白合受体 (aGPCR) 在生理过程中起着至关重要的作用.
- 许多aGPCR的激活涉及一个内部绑定的激动剂,Stachel序列.
研究的目的:
- 确定与Gs复合的GPR133和GPR114的冷电子显微镜 (cryo-EM) 结构.
- 阐明Stachel序列介导的aGPCR激活和Gs合的分子机制.
主要方法:
- 低温电子显微镜 (cryo-EM) 用于结构的确定.
- 参与受体激活的关键动机的生物化学特征.
主要成果:
- 确定了GPR133-Gs和GPR114-Gs复合物的冷EM结构.
- 揭示了Stachel序列采用α-螺旋-凸-β-片结构,并在跨膜域内结合.
- 确定了一种对Stachel-TMD相互作用至关重要的疏水性相互作用动机 (HIM).
- 阐明了维护开关 (W6.53) 和键网络在Stachel传感和Gs合中的作用.
- 观察到一个共同的Gs结合接口,GPR114通过扩展的TM7表现出独特的Gs相互作用.
结论:
- 斯塔克尔序列的结构及其与TMD的相互作用对于aGPCR激活至关重要.
- 特定的分子相互作用,包括HIM,切换开关和键网络,控制Stachel序列识别和Gs合.
- 这些发现为GPCR激活和信号通路提供了详细的机制见解.
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