Molecular features of the ligand-free GLP-1R, GCGR and GIPR in complex with Gs proteins.

IF 13 1区 生物学 Q1 CELL BIOLOGY
Zhaotong Cong, Fenghui Zhao, Yang Li, Gan Luo, Yiting Mai, Xianyue Chen, Yanyan Chen, Shi Lin, Xiaoqing Cai, Qingtong Zhou, Dehua Yang, Ming-Wei Wang
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Abstract

Class B1 G protein-coupled receptors (GPCRs) are important regulators of many physiological functions such as glucose homeostasis, which is mainly mediated by three peptide hormones, i.e., glucagon-like peptide-1 (GLP-1), glucagon (GCG), and glucose-dependent insulinotropic polypeptide (GIP). They trigger a cascade of signaling events leading to the formation of an active agonist-receptor-G protein complex. However, intracellular signal transducers can also activate the receptor independent of extracellular stimuli, suggesting an intrinsic role of G proteins in this process. Here, we report cryo-electron microscopy structures of the human GLP-1 receptor (GLP-1R), GCG receptor (GCGR), and GIP receptor (GIPR) in complex with Gs proteins without the presence of cognate ligands. These ligand-free complexes share a similar intracellular architecture to those bound by endogenous peptides, in which, the Gs protein alone directly opens the intracellular binding cavity and rewires the extracellular orthosteric pocket to stabilize the receptor in a state unseen before. While the peptide-binding site is partially occupied by the inward folded transmembrane helix 6 (TM6)-extracellular loop 3 (ECL3) juncture of GIPR or a segment of GCGR ECL2, the extracellular portion of GLP-1R adopts a conformation close to the active state. Our findings offer valuable insights into the distinct activation mechanisms of these three important receptors. It is possible that in the absence of a ligand, the intracellular half of transmembrane domain is mobilized with the help of Gs protein, which in turn rearranges the extracellular half to form a transitional conformation, facilitating the entry of the peptide N-terminus.

Abstract Image

无配体 GLP-1R、GCGR 和 GIPR 与 Gs 蛋白复合的分子特征。
B1 类 G 蛋白偶联受体(GPCR)是许多生理功能(如葡萄糖平衡)的重要调节器,葡萄糖平衡主要由三种肽类激素(即胰高血糖素样肽-1(GLP-1)、胰高血糖素(GCG)和葡萄糖依赖性促胰岛素多肽(GIP))介导。它们会触发一连串的信号传导事件,从而形成活跃的激动剂-受体-G 蛋白复合物。然而,细胞内的信号转导物也能激活受体,而不受细胞外刺激的影响,这表明 G 蛋白在这一过程中发挥着内在作用。在这里,我们报告了人类 GLP-1 受体(GLP-1R)、GCG 受体(GCGR)和 GIP 受体(GIPR)在没有同源配体存在的情况下与 Gs 蛋白复合物的冷冻电镜结构。这些不含配体的复合物具有与内源性肽结合的复合物相似的细胞内结构,其中,Gs 蛋白单独直接打开细胞内结合腔,并重新连接细胞外正交口袋,使受体稳定在前所未有的状态。肽结合位点部分被 GIPR 向内折叠的跨膜螺旋 6(TM6)-细胞外环 3(ECL3)连接点或 GCGR ECL2 的一段占据,而 GLP-1R 的细胞外部分则采用了接近活性状态的构象。我们的发现为了解这三种重要受体的不同激活机制提供了宝贵的见解。在没有配体的情况下,跨膜结构域的胞内部分可能在 Gs 蛋白的帮助下被调动起来,进而重新排列胞外部分以形成过渡构象,从而促进多肽 N 端的进入。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Cell Discovery
Cell Discovery Biochemistry, Genetics and Molecular Biology-Molecular Biology
CiteScore
24.20
自引率
0.60%
发文量
120
审稿时长
20 weeks
期刊介绍: Cell Discovery is a cutting-edge, open access journal published by Springer Nature in collaboration with the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences (CAS). Our aim is to provide a dynamic and accessible platform for scientists to showcase their exceptional original research. Cell Discovery covers a wide range of topics within the fields of molecular and cell biology. We eagerly publish results of great significance and that are of broad interest to the scientific community. With an international authorship and a focus on basic life sciences, our journal is a valued member of Springer Nature's prestigious Molecular Cell Biology journals. In summary, Cell Discovery offers a fresh approach to scholarly publishing, enabling scientists from around the world to share their exceptional findings in molecular and cell biology.
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