IDEAS home Printed from https://ideas.repec.org/a/nat/nature/v546y2017i7656d10.1038_nature22327.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/nature22327
    File Function: Abstract
    Download Restriction: Access to the full text of the articles in this series is restricted.
    File URL: https://libkey.io/10.1038/nature22327?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    As the access to this document is restricted, you may want to search for a different version of it.

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. 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.
    2. 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.
    3. 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.
    4. 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.
    5. 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.
    6. 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.
    7. 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.
    8. 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.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:nature:v:546:y:2017:i:7656:d:10.1038_nature22327. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.