Human GLP-1 receptor transmembrane domain structure in complex with allosteric modulators

Gaojie Song, Dehua Yang, Yuxia Wang, C. 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 LiuMing Wei Wang, Raymond C. Stevens*

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

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 Å 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.

Original languageEnglish
Pages (from-to)312-315
Number of pages4
JournalNature
Volume546
Issue number7657
DOIs
Publication statusPublished - 8 Jun 2017

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