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Conformational rearrangement during activation of a metabotropic glutamate receptor.

代谢型谷氨酸受体激活过程中的构象重排。

  • 影响因子:9.33
  • DOI:10.1038/s41589-020-00702-5
  • 作者列表:"Liauw BW","Afsari HS","Vafabakhsh R
  • 发表时间:2021-03-01
Abstract

:G protein-coupled receptors (GPCRs) relay information across cell membranes through conformational coupling between the ligand-binding domain and cytoplasmic signaling domain. In dimeric class C GPCRs, the mechanism of this process, which involves propagation of local ligand-induced conformational changes over 12 nm through three distinct structural domains, is unknown. Here, we used single-molecule FRET and live-cell imaging and found that metabotropic glutamate receptor 2 (mGluR2) interconverts between four conformational states, two of which were previously unknown, and activation proceeds through the conformational selection mechanism. Furthermore, the conformation of the ligand-binding domains and downstream domains are weakly coupled. We show that the intermediate states act as conformational checkpoints for activation and control allosteric modulation of signaling. Our results demonstrate a mechanism for activation of mGluRs where ligand binding controls the proximity of signaling domains, analogous to some receptor kinases. This design principle may be generalizable to other biological allosteric sensors.

摘要

: g蛋白偶联受体 (gpcr) 通过配体结合域和细胞质信号传导域之间的构象偶联跨细胞膜传递信息。在二聚C类gpcr中,这一过程的机制是未知的,该过程涉及局部配体诱导的构象变化在12纳米以上通过三个不同的结构域传播。在这里,我们使用单分子FRET和活细胞成像,发现代谢型谷氨酸受体2 (mGluR2) 在四种构象状态之间相互转换,其中两种之前未知,激活通过构象选择机制进行。此外,配体结合结构域和下游结构域的构象是弱偶联的。我们表明,中间状态充当激活和控制信号的变构调节的构象检查点。我们的结果证明了mGluRs的激活机制,其中配体结合控制信号传导结构域的接近,类似于一些受体激酶。该设计原理可以推广到其他生物变构传感器。

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