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

Author

Listed:
  • Fai Yiu Siu

    (The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA)

  • Min He

    (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)

  • Chris de Graaf

    (Faculty of Sciences, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), VU University of Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands)

  • Gye Won Han

    (The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA)

  • Dehua Yang

    (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)

  • Zhiyun Zhang

    (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)

  • Caihong Zhou

    (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)

  • Qingping Xu

    (The Joint Center for Structural Genomics, Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, Menlo Park, California 94025, USA)

  • Daniel Wacker

    (The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA)

  • Jeremiah S. Joseph

    (The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA)

  • Wei Liu

    (The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA)

  • Jesper Lau

    (Protein & Peptide Chemistry, Novo Nordisk, Novo Nordisk Park, 2760 Malov, Denmark)

  • Vadim Cherezov

    (The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA)

  • Vsevolod Katritch

    (The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA)

  • Ming-Wei Wang

    (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)

  • Raymond C. Stevens

    (The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA)

Abstract

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.

Suggested Citation

  • Fai Yiu Siu & Min He & Chris de Graaf & Gye Won Han & Dehua Yang & Zhiyun Zhang & Caihong Zhou & Qingping Xu & Daniel Wacker & Jeremiah S. Joseph & Wei Liu & Jesper Lau & Vadim Cherezov & Vsevolod Kat, 2013. "Structure of the human glucagon class B G-protein-coupled receptor," Nature, Nature, vol. 499(7459), pages 444-449, July.
    • Handle: RePEc:nat:nature:v:499:y:2013:i:7459:d:10.1038_nature12393
    DOI: 10.1038/nature12393
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    Cited by:

    1. Chris Habrian & Naomi Latorraca & Zhu Fu & Ehud Y. Isacoff, 2023. "Homo- and hetero-dimeric subunit interactions set affinity and efficacy in metabotropic glutamate receptors," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
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    3. Fenghui Zhao & Qingtong Zhou & Zhaotong Cong & Kaini Hang & Xinyu Zou & Chao Zhang & Yan Chen & Antao Dai & Anyi Liang & Qianqian Ming & Mu Wang & Li-Nan Chen & Peiyu Xu & Rulve Chang & Wenbo Feng & T, 2022. "Structural insights into multiplexed pharmacological actions of tirzepatide and peptide 20 at the GIP, GLP-1 or glucagon receptors," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    4. Sathvik Anantakrishnan & Athi N. Naganathan, 2023. "Thermodynamic architecture and conformational plasticity of GPCRs," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
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    7. Shivani Sachdev & Brendan A. Creemer & Thomas J. Gardella & Ross W. Cheloha, 2024. "Highly biased agonism for GPCR ligands via nanobody tethering," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    8. Elizaveta Lyapina & Egor Marin & Anastasiia Gusach & Philipp Orekhov & Andrey Gerasimov & Aleksandra Luginina & Daniil Vakhrameev & Margarita Ergasheva & Margarita Kovaleva & Georgii Khusainov & Polin, 2022. "Structural basis for receptor selectivity and inverse agonism in S1P5 receptors," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

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