Journal Article

Structure of the full-length glucagon class B G-protein-coupled receptor

Weierstall, Uwe, Cherezov, Vadim, Zhang, Hui, Dong, Yuhui, Wu, Xiaoai, Yang, Dehua, Wang, Ming-Wei, Zhao, Qiang, Dai, Antao, Wu, Yanhong, Ma, Limin, Dharmarajan, Venkatasubramanian, Sierra, Raymond G., Wu, Beili, Reedtz-Runge, Steffen, Song, Gaojie, Lau, Jesper, Griffin, Patrick R., Liu, Wei, Lin, Guangyao, Han, Gye Won, Cai, Xiaoqing, Geng, Zhi, Qiao, Anna, Yang, Huaiyu, Hanson, Michael A., Stevens, Raymond C., Nelson, Garrett, Zhang, Haonan, de Graaf, Chris, Grant, Thomas D., Yang, Linlin, Jiang, Hualiang

2017

Overview

The human glucagon receptor, GCGR, belongs to the class B G-protein-coupled receptor family and plays a key role in glucose homeostasis and the pathophysiology of type 2 diabetes. Here we report the 3.0 Å crystal structure of full-length GCGR containing both the extracellular domain and transmembrane domain in an inactive conformation. The two domains are connected by a 12-residue segment termed the stalk, which adopts a β-strand conformation, instead of forming an α-helix as observed in the previously solved structure of the GCGR transmembrane domain. The first extracellular loop exhibits a β-hairpin conformation and interacts with the stalk to form a compact β-sheet structure. Hydrogen–deuterium exchange, disulfide crosslinking and molecular dynamics studies suggest that the stalk and the first extracellular loop have critical roles in modulating peptide ligand binding and receptor activation. These insights into the full-length GCGR structure deepen our understanding of the signalling mechanisms of class B G-protein-coupled receptors. The crystal structure of the full-length human glucagon receptor reveals the essential role of the 12-residue ‘stalk’ segment and an extracellular loop in the regulation of ligand binding and receptor activation. Full-length class B GPCR structures The glucagon-like peptide-1 receptor (GLP-1R) and the glucagon receptor (GCGR) belong to the class B G-protein-coupled receptor family and have opposing physiological roles in glucose homeostasis and insulin release. As such, they are important in regulating metabolism and appetite and offer significant treatment possibilities for type 2 diabetes. However, as yet, no full-length structures of these receptors have been solved. Three papers in this issue of Nature report the structure of GLP-1R. Ray Stevens and colleagues describe the crystal structure of the human GLP-1R transmembrane domain in an inactive state in complex with negative allosteric modulators. Fiona Marshall and colleagues describe the active-state full-length receptor in complex with truncated peptide agonists, which have potent activity in mice on oral administration. Georgios Skiniotis, Brian Kobilka and colleagues describe the cryo-electron microscopy structure of an unmodified GLP-1R in complex with its endogenous peptide ligand, GLP-1, and the heterotrimeric G protein. Finally, in a fourth paper in this week's issue of Nature , Beili Wu and colleagues report the crystal structure of the full-length GCGR in an inactive conformation. Taken together, these studies provide key insights into the activation and signalling mechanisms of class B receptors and provide therapeutic opportunities for targeting this receptor family.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 101/47 / 13/31 / 13/44 / 38/23 / 631/45/535/1266 / 631/535/1266 / 82/80 / 82/83 / 96/34 / 96/95 / Activation / Allosteric Site - drug effects / Benzamides - chemistry / Benzamides - metabolism / Benzamides - pharmacology / Cell Membrane - metabolism / Coupling (molecular) / Cross-Linking Reagents - chemistry / Crosslinking / Crystal structure / Crystallography, X-Ray / Deuterium / Deuterium Exchange Measurement / Diabetes / Diabetes mellitus / Disulfides - chemistry / Exchanging / Forming / G protein-coupled receptors / G proteins / Glucagon / Glucose / Guanine nucleotide-binding protein / Health aspects / Homeostasis / Humanities and Social Sciences / Humans / Hydrogen / Hydrogen-deuterium exchange / Ligands / Methods / Models, Molecular / Molecular dynamics / Molecular Dynamics Simulation / Molecular structure / multidisciplinary / Phenylurea Compounds - chemistry / Phenylurea Compounds - metabolism / Phenylurea Compounds - pharmacology / Protein Domains / Protein Stability / Protein structure / Protein structure prediction / Proteins / Receptor mechanisms / Receptors / Receptors, Glucagon - agonists / Receptors, Glucagon - chemistry / Receptors, Glucagon - classification / Receptors, Glucagon - metabolism / Science / Signaling / Structure