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

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

Research output: Contribution to journalArticle

83 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)259-264
Number of pages6
JournalNature
Volume546
Issue number7657
DOIs
StatePublished - Jun 8 2017

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ASJC Scopus subject areas

  • Medicine(all)
  • General

Cite this

Zhang, H., Qiao, A., Yang, D., Yang, L., Dai, A., De Graaf, C., Reedtz-Runge, S., Dharmarajan, V., Zhang, H., Han, G. W., Grant, T. D., Sierra, R. G., Weierstall, U., Nelson, G., Liu, W., Wu, Y., Ma, L., Cai, X., Lin, G., ... Wu, B. (2017). Structure of the full-length glucagon class B G-protein-coupled receptor. Nature, 546(7657), 259-264. https://doi.org/10.1038/nature22363