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 () and Beili Wu ()
Additional contact information
Haonan Zhang: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Anna Qiao: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Dehua Yang: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Linlin Yang: School of Basic Medical Sciences, Zhengzhou University
Antao Dai: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Chris de Graaf: Faculty of Sciences, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Vrije Universiteit Amsterdam
Steffen Reedtz-Runge: Novo Nordisk A/S, Novo Nordisk Park
Venkatasubramanian Dharmarajan: The Scripps Research Institute
Hui Zhang: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Gye Won Han: Bridge Institute, University of Southern California
Thomas D. Grant: Hauptman–Woodward Institute, SUNY at Buffalo
Raymond G. Sierra: Linac Coherent Light Source (LCLS), SLAC National Accelerator Laboratory
Uwe Weierstall: Arizona State University
Garrett Nelson: Arizona State University
Wei Liu: Biodesign Center for Applied Structural Discovery, Biodesign Institute, School of Molecular Sciences, Arizona State University
Yanhong Wu: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Limin Ma: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Xiaoqing Cai: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Guangyao Lin: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Xiaoai Wu: Novo Nordisk Research Centre China
Zhi Geng: Beijing Synchrotron Radiation Facility, Institute of High Energy Physics, Chinese Academy of Sciences
Yuhui Dong: Beijing Synchrotron Radiation Facility, Institute of High Energy Physics, Chinese Academy of Sciences
Gaojie Song: iHuman Institute, ShanghaiTech University
Patrick R. Griffin: The Scripps Research Institute
Jesper Lau: Novo Nordisk A/S, Novo Nordisk Park
Vadim Cherezov: Bridge Institute, University of Southern California
Huaiyu Yang: Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Michael A. Hanson: GPCR Consortium
Raymond C. Stevens: School of Life Science and Technology, ShanghaiTech University
Qiang Zhao: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Hualiang Jiang: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Ming-Wei Wang: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Beili Wu: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences

Nature, 2017, vol. 546, issue 7657, 259-264

Abstract: 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.

Date: 2017
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DOI: 10.1038/nature22363

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