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 Wu; Zhi 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

doi:10.1038/nature22363

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

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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 language	English (US)
Pages (from-to)	259-264
Number of pages	6
Journal	Nature
Volume	546
Issue number	7657
DOIs	https://doi.org/10.1038/nature22363
State	Published - Jun 8 2017

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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

Zhang, H, Qiao, A, Yang, D, Yang, L, Dai, A, De Graaf, C, Reedtz-Runge, S, Dharmarajan, V, Zhang, H, Han, GW, Grant, TD, Sierra, RG, Weierstall, U, Nelson, G, Liu, W, Wu, Y, Ma, L, Cai, X, Lin, G, Wu, X, Geng, Z, Dong, Y, Song, G, Griffin, PR, Lau, J, Cherezov, V, Yang, H, Hanson, MA, Stevens, RC, Zhao, Q, Jiang, H, Wang, MW & Wu, B 2017, 'Structure of the full-length glucagon class B G-protein-coupled receptor', Nature, vol. 546, no. 7657, pp. 259-264. https://doi.org/10.1038/nature22363

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title = "Structure of the full-length glucagon class B G-protein-coupled receptor",

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 {\AA} 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.",

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

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AU - Yang, Dehua

AU - Yang, Linlin

AU - Dai, Antao

AU - De Graaf, Chris

AU - Reedtz-Runge, Steffen

AU - Dharmarajan, Venkatasubramanian

AU - Zhang, Hui

AU - Han, Gye Won

AU - Grant, Thomas D.

AU - Sierra, Raymond G.

AU - Weierstall, Uwe

AU - Nelson, Garrett

AU - Liu, Wei

AU - Wu, Yanhong

AU - Ma, Limin

AU - Cai, Xiaoqing

AU - Lin, Guangyao

AU - Wu, Xiaoai

AU - Geng, Zhi

AU - Dong, Yuhui

AU - Song, Gaojie

AU - Griffin, Patrick R.

AU - Lau, Jesper

AU - Cherezov, Vadim

AU - Yang, Huaiyu

AU - Hanson, Michael A.

AU - Stevens, Raymond C.

AU - Zhao, Qiang

AU - Jiang, Hualiang

AU - Wang, Ming Wei

AU - Wu, Beili

PY - 2017/6/8

Y1 - 2017/6/8

N2 - 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.

AB - 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.

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

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