Structure of the human glucagon class B G-protein-coupled receptor

  • Nature volume 499, pages 444449 (25 July 2013)
  • doi:10.1038/nature12393
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Binding of the glucagon peptide to the glucagon receptor (GCGR) triggers the release of glucose from the liver during fasting; thus GCGR plays an important role in glucose homeostasis. Here we report the crystal structure of the seven transmembrane helical domain of human GCGR at 3.4 Å resolution, complemented by extensive site-specific mutagenesis, and a hybrid model of glucagon bound to GCGR to understand the molecular recognition of the receptor for its native ligand. Beyond the shared seven transmembrane fold, the GCGR transmembrane domain deviates from class A G-protein-coupled receptors with a large ligand-binding pocket and the first transmembrane helix having a ‘stalk’ region that extends three alpha-helical turns above the plane of the membrane. The stalk positions the extracellular domain (12 kilodaltons) relative to the membrane to form the glucagon-binding site that captures the peptide and facilitates the insertion of glucagon’s amino terminus into the seven transmembrane domain.

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Protein Data Bank

Data deposits

The coordinates and the structure factors have been deposited in the Protein Data Bank under the accession code 4L6R.


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This work was supported by NIH Roadmap grant P50 GM073197 for technology development (V.C. and R.C.S.), and PSI:Biology grant U54 GM094618 for biological studies and structure production (target GPCR-49) (V.K., V.C. and R.C.S.); PSI:Biology grant U54 GM094586 for structure QC; The Ministry of Health grants 2012ZX09304-011 and 2013ZX09507002 (M.-W.W.), Shanghai Science and Technology Development Fund 11DZ2292200 (M.-W.W.); Novo Nordisk-Chinese Academy of Sciences Research Fund NNCAS-2011-7 (M.-W.W.); Thousand Talents Program in China (R.C.S. and M.-W.W.); NIH Postdoctoral Training Grant (NRSA) F32 DK088392 (F.Y.S.); The Netherlands Organization for Scientific Research (NWO) through a VENI grant (Grant 700.59.408 to C.d.G.); COST Action CM1207, GLISTEN (C.d.G). We also thank V. Hruby and M. Cai for advice with the glucagon binding assay and general discussions; J. Velasquez for help with molecular biology; T. Trinh and M. Chu for help with baculovirus expression; K. Kadyshevskaya for assistance with figure preparation; X. Q. Cai, J. Wang, Y. Feng, A. T. Dai, Y. Zhou, J. J. Deng, Y. B. Dai and J. W. Zhao for technical assistance in mutation studies; A. Walker for assistance with manuscript preparation; and J. Smith and R. Fischetti for assistance in development and use of the minibeam and beamtime at GM/CA-CAT beamline 23-ID at the Advanced Photon Source, which is supported by National Cancer Institute grant Y1-CO-1020 and National Institute of General Medical Sciences grant Y1-GM-1104.

Author information


  1. Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA

    • Fai Yiu Siu
    • , Gye Won Han
    • , Daniel Wacker
    • , Jeremiah S. Joseph
    • , Wei Liu
    • , Vadim Cherezov
    • , Vsevolod Katritch
    •  & Raymond C. Stevens
  2. The National Center for Drug Screening and the CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), 189 Guo Shou Jing Road, Shanghai, 201203, China

    • Min He
    • , Dehua Yang
    • , Zhiyun Zhang
    • , Caihong Zhou
    •  & Ming-Wei Wang
  3. Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), VU University of Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands

    • Chris de Graaf
  4. The Joint Center for Structural Genomics, Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, Menlo Park, California 94025, USA

    • Qingping Xu
  5. Protein & Peptide Chemistry, Novo Nordisk, Novo Nordisk Park, 2760 Malov, Denmark

    • Jesper Lau


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F.Y.S. designed, expressed, characterized and screened constructs and ligands for crystallization. F.Y.S. purified and crystallized the receptor in LCP, optimized crystallization conditions, grew crystals, collected diffraction data and prepared the manuscript. G.W.H. and Q.X. solved and refined the structure, and prepared the manuscript. V.C. collected and processed diffraction data, and prepared the manuscript. M.H., D.Y., Z.Z. and C.Z. expressed the receptor, and performed the mutagenesis and ligand-binding assay. V.K. and C.d.G. designed and analysed the receptor mutagenesis studies, constructed the receptor–ligand model and prepared the manuscript. D.W. and J.S.J. collected and processed SAD data and determined an initial electron density map from experimental phases. W.L. and V.C. trained and assisted in LCP crystallization. J.L. provided ligands for GCGR and prepared the manuscript. R.C.S., F.Y.S., M.-W.W., V.K., V.C. and C.d.G. were responsible for the overall project strategy and management and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Ming-Wei Wang or Raymond C. Stevens.

Supplementary information

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    Supplementary Information

    This file contains Supplementary Tables 1-6, Supplementary Figures 1-10 and Supplementary References.


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