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Phase-plate cryo-EM structure of a class B GPCR–G-protein complex

Author

Listed:
  • Yi-Lynn Liang

    (Monash Institute of Pharmaceutical Sciences, Monash University)

  • Maryam Khoshouei

    (Max Planck Institute of Biochemistry)

  • Mazdak Radjainia

    (Monash University
    FEI)

  • Yan Zhang

    (University of Michigan Medical School)

  • Alisa Glukhova

    (Monash Institute of Pharmaceutical Sciences, Monash University)

  • Jeffrey Tarrasch

    (University of Michigan Medical School)

  • David M. Thal

    (Monash Institute of Pharmaceutical Sciences, Monash University)

  • Sebastian G. B. Furness

    (Monash Institute of Pharmaceutical Sciences, Monash University)

  • George Christopoulos

    (Monash Institute of Pharmaceutical Sciences, Monash University)

  • Thomas Coudrat

    (Monash Institute of Pharmaceutical Sciences, Monash University)

  • Radostin Danev

    (Max Planck Institute of Biochemistry)

  • Wolfgang Baumeister

    (Max Planck Institute of Biochemistry)

  • Laurence J. Miller

    (Mayo Clinic)

  • Arthur Christopoulos

    (Monash Institute of Pharmaceutical Sciences, Monash University)

  • Brian K. Kobilka

    (Stanford University School of Medicine)

  • Denise Wootten

    (Monash Institute of Pharmaceutical Sciences, Monash University)

  • Georgios Skiniotis

    (University of Michigan Medical School)

  • Patrick M. Sexton

    (Monash Institute of Pharmaceutical Sciences, Monash University)

Abstract

Class B G-protein-coupled receptors are major targets for the treatment of chronic diseases, such as osteoporosis, diabetes and obesity. Here we report the structure of a full-length class B receptor, the calcitonin receptor, in complex with peptide ligand and heterotrimeric Gαsβγ protein determined by Volta phase-plate single-particle cryo-electron microscopy. The peptide agonist engages the receptor by binding to an extended hydrophobic pocket facilitated by the large outward movement of the extracellular ends of transmembrane helices 6 and 7. This conformation is accompanied by a 60° kink in helix 6 and a large outward movement of the intracellular end of this helix, opening the bundle to accommodate interactions with the α5-helix of Gαs. Also observed is an extended intracellular helix 8 that contributes to both receptor stability and functional G-protein coupling via an interaction with the Gβ subunit. This structure provides a new framework for understanding G-protein-coupled receptor function.

Suggested Citation

  • Yi-Lynn Liang & Maryam Khoshouei & Mazdak Radjainia & Yan Zhang & Alisa Glukhova & Jeffrey Tarrasch & David M. Thal & Sebastian G. B. Furness & George Christopoulos & Thomas Coudrat & Radostin Danev &, 2017. "Phase-plate cryo-EM structure of a class B GPCR–G-protein complex," Nature, Nature, vol. 546(7656), pages 118-123, June.
    • Handle: RePEc:nat:nature:v:546:y:2017:i:7656:d:10.1038_nature22327
    DOI: 10.1038/nature22327
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    Citations

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    Cited by:

    1. Na Wang & Xinheng He & Jing Zhao & Hualiang Jiang & Xi Cheng & Yu Xia & H. Eric Xu & Yuanzheng He, 2022. "Structural basis of leukotriene B4 receptor 1 activation," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    2. Kaihua Zhang & Hao Wu & Nicholas Hoppe & Aashish Manglik & Yifan Cheng, 2022. "Fusion protein strategies for cryo-EM study of G protein-coupled receptors," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    3. Xudong Wang & Chris Neale & Soo-Kyung Kim & William A. Goddard & Libin Ye, 2023. "Intermediate-state-trapped mutants pinpoint G protein-coupled receptor conformational allostery," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    4. Yong-Seok Kim & Jun-Hee Yeon & Woori Ko & Byung-Chang Suh, 2023. "Two-step structural changes in M3 muscarinic receptor activation rely on the coupled Gq protein cycle," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    5. Julien Bous & Julia Kinsolving & Lukas Grätz & Magdalena M. Scharf & Jan Hendrik Voss & Berkay Selcuk & Ogün Adebali & Gunnar Schulte, 2024. "Structural basis of frizzled 7 activation and allosteric regulation," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    6. Jie Yin & Yanyong Kang & Aaron P. McGrath & Karen Chapman & Megan Sjodt & Eiji Kimura & Atsutoshi Okabe & Tatsuki Koike & Yuhei Miyanohana & Yuji Shimizu & Rameshu Rallabandi & Peng Lian & Xiaochen Ba, 2022. "Molecular mechanism of the wake-promoting agent TAK-925," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    7. Michael W. Martynowycz & Anna Shiriaeva & Max T. B. Clabbers & William J. Nicolas & Sara J. Weaver & Johan Hattne & Tamir Gonen, 2023. "A robust approach for MicroED sample preparation of lipidic cubic phase embedded membrane protein crystals," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    8. Li-Hua Zhao & Jingyu Lin & Su-Yu Ji & X. Edward Zhou & Chunyou Mao & Dan-Dan Shen & Xinheng He & Peng Xiao & Jinpeng Sun & Karsten Melcher & Yan Zhang & Xiao Yu & H. Eric Xu, 2022. "Structure insights into selective coupling of G protein subtypes by a class B G protein-coupled receptor," Nature Communications, Nature, vol. 13(1), pages 1-13, December.

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