4 years ago

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

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

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.

Publisher URL: http://dx.doi.org/10.1038/nature22363

DOI: 10.1038/nature22363

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