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研究揭示代谢型谷氨酸受体介导的G蛋白激活
2021-07-04 13:57

美国斯坦福大学Georgios Skiniotis等研究人员合作揭示代谢型谷氨酸受体介导的G蛋白激活。相关论文于2021年6月30日在线发表在《自然》杂志上。

据研究人员介绍,C家族G蛋白偶联受体(GPCR)作为具有识别小配体的细胞外结构域的专性二聚体起作用,并通过未知机制导致这些受体跨膜(TM)结构域上的G蛋白激活。

研究人员报道了C家族代谢型谷氨酸受体2(mGlu2)的同源二聚体在不同功能状态下以及与异源三聚体Gi结合时的结构。细胞外结构域激活后,两个跨膜结构域在相对方向上发生广泛的重排,从而建立不对称的TM6-TM6界面,并促进一个原聚体在细胞质结构域的构象变化。

可以观察到核苷酸结合的Gi与非活性mGlu2预耦合,但它向无核苷酸形式的转变似乎取决于建立活性状态TM6-TM6界面。与A家族和B家族GPCR相比,G蛋白偶联不涉及TM6的细胞质开放,而是通过细胞内环2和3的协调以及受体C末端的关键贡献来促进。这些发现突出了全局和局部构象转变的协同作用,进而促进新的G蛋白激活模式。

附:英文原文

Title: G-protein activation by a metabotropic glutamate receptor

Author: Alpay B. Seven, Ximena Barros-lvarez, Marine de Lapeyrire, Makaa M. Papasergi-Scott, Michael J. Robertson, Chensong Zhang, Robert M. Nwokonko, Yang Gao, Justin G. Meyerowitz, Jean-Philippe Rocher, Dominik Schelshorn, Brian K. Kobilka, Jesper M. Mathiesen, Georgios Skiniotis

Issue&Volume: 2021-06-30

Abstract: Family C G-protein-coupled receptors (GPCRs) operate as obligate dimers with extracellular domains that recognize small ligands, leading to G-protein activation on the transmembrane (TM) domains of these receptors by an unknown mechanism1. Here we show structures of homodimers of the family C metabotropic glutamate receptor 2 (mGlu2) in distinct functional states and in complex with heterotrimeric Gi. Upon activation of the extracellular domain, the two transmembrane domains undergo extensive rearrangement in relative orientation to establish an asymmetric TM6–TM6 interface that promotes conformational changes in the cytoplasmic domain of one protomer. Nucleotide-bound Gi can be observed pre-coupled to inactive mGlu2, but its transition to the nucleotide-free form seems to depend on establishing the active-state TM6–TM6 interface. In contrast to family A and B GPCRs, G-protein coupling does not involve the cytoplasmic opening of TM6 but is facilitated through the coordination of intracellular loops 2 and 3, as well as a critical contribution from the C terminus of the receptor. The findings highlight the synergy of global and local conformational transitions to facilitate a new mode of G-protein activation.

DOI: 10.1038/s41586-021-03680-3

Source: https://www.nature.com/articles/s41586-021-03680-3

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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