2. Academic Validation
  3. Structure of the full-length glucagon class B G-protein-coupled receptor

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

  • Nature. 2017 Jun 8;546(7657):259-264. doi: 10.1038/nature22363.
Haonan Zhang 1 2,  Anna Qiao 1 2,  Dehua Yang 1 3,  Linlin Yang 4,  Antao Dai 1 3,  Chris de Graaf 5,  Steffen Reedtz-Runge 6,  Venkatasubramanian Dharmarajan 7,  Hui Zhang 1 2,  Gye Won Han 8,  Thomas D Grant 9,  Raymond G Sierra 10,  Uwe Weierstall 11,  Garrett Nelson 11,  Wei Liu 12,  Yanhong Wu 1 2 13,  Limin Ma 1,  Xiaoqing Cai 1 3,  Guangyao Lin 1 2 3 13,  Xiaoai Wu 14,  Zhi Geng 15,  Yuhui Dong 15,  Gaojie Song 16,  Patrick R Griffin 7,  Jesper Lau 6,  Vadim Cherezov 8,  Huaiyu Yang 17,  Michael A Hanson 18,  Raymond C Stevens 13 16,  Qiang Zhao 1 2 19 20,  Hualiang Jiang 1 17 19,  Ming-Wei Wang 1 3 13 21,  Beili Wu 1 2 13 20
Affiliations

Affiliations

  • 1 CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai 201203, China.
  • 2 University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
  • 3 The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 189 Guo Shou Jing Road, Pudong, Shanghai 201203, China.
  • 4 Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, 100 Science Avenue, Zhengzhou 450001, China.
  • 5 Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1108, Amsterdam 1081 HZ, The Netherlands.
  • 6 Novo Nordisk A/S, Novo Nordisk Park, Måløv 2760, Denmark.
  • 7 Department of Molecular Medicine, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, USA.
  • 8 Department of Chemistry, Bridge Institute, University of Southern California, 3430 S. Vermont Avenue, Los Angeles, California 90089, USA.
  • 9 Hauptman-Woodward Institute, SUNY at Buffalo, 700 Ellicott Street, Buffalo, New York 14203, USA.
  • 10 Linac Coherent Light Source (LCLS), SLAC National Accelerator Laboratory, Menlo Park, California 94025, USA.
  • 11 Department of Physics, Arizona State University, Tempe, Arizona 85287, USA.
  • 12 Biodesign Center for Applied Structural Discovery, Biodesign Institute, School of Molecular Sciences, Arizona State University, Tempe, Arizona 85287, USA.
  • 13 School of Life Science and Technology, ShanghaiTech University, 393 Hua Xia Zhong Road, Pudong, Shanghai 201210, China.
  • 14 Novo Nordisk Research Centre China, No. 20 Life Science Park Road, Changping District, Beijing 102206, China.
  • 15 Beijing Synchrotron Radiation Facility, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing 100049, China.
  • 16 iHuman Institute, ShanghaiTech University, 393 Hua Xia Zhong Road, Shanghai 201210, China.
  • 17 Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai 201203, China.
  • 18 GPCR Consortium, San Marcos, California 92078, USA.
  • 19 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai 201203, China.
  • 20 CAS Center for Excellence in Biomacromolecules, Chinese Academy of Sciences, Beijing 100101, China.
  • 21 School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
PMID: 28514451 DOI: 10.1038/nature22363
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.

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