变构调节
G蛋白偶联受体
异三聚体G蛋白
胰高血糖素样肽1受体
跨膜结构域
胰高血糖素受体
化学
受体
细胞生物学
生物化学
兴奋剂
生物
G蛋白
胰高血糖素
激素
作者
Gaojie Song,Dehua Yang,Yuxia Wang,Chris de Graaf,Qingtong Zhou,Shanshan Jiang,Kaiwen Liu,Xiaoqing Cai,Antao Dai,Guangyao Lin,Dongsheng Liu,Fan Wu,Yiran Wu,Suwen Zhao,Li Ye,Gye Won Han,Jesper Lau,Beili Wu,Michael A. Hanson,Zhi‐Jie Liu,Ming‐Wei Wang,Raymond C. Stevens
出处
期刊:Nature
[Springer Nature]
日期:2017-05-17
卷期号:546 (7657): 312-315
被引量:207
摘要
The glucagon-like peptide-1 receptor (GLP-1R) and the glucagon receptor (GCGR) are members of the secretin-like class B family of G-protein-coupled receptors (GPCRs) and have opposing physiological roles in insulin release and glucose homeostasis. The treatment of type 2 diabetes requires positive modulation of GLP-1R to inhibit glucagon secretion and stimulate insulin secretion in a glucose-dependent manner. Here we report crystal structures of the human GLP-1R transmembrane domain in complex with two different negative allosteric modulators, PF-06372222 and NNC0640, at 2.7 and 3.0 A resolution, respectively. The structures reveal a common binding pocket for negative allosteric modulators, present in both GLP-1R and GCGR and located outside helices V-VII near the intracellular half of the receptor. The receptor is in an inactive conformation with compounds that restrict movement of the intracellular tip of helix VI, a movement that is generally associated with activation mechanisms in class A GPCRs. Molecular modelling and mutagenesis studies indicate that agonist positive allosteric modulators target the same general region, but in a distinct sub-pocket at the interface between helices V and VI, which may facilitate the formation of an intracellular binding site that enhances G-protein coupling.
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