IDEAS home Printed from https://ideas.repec.org/a/nat/nature/v595y2021i7867d10.1038_s41586-021-03691-0.html
   My bibliography  Save this article

Asymmetric activation of the calcium-sensing receptor homodimer

Author

Listed:
  • Yang Gao

    (Stanford University School of Medicine
    Stanford University School of Medicine)

  • Michael J. Robertson

    (Stanford University School of Medicine
    Stanford University School of Medicine)

  • Sabrina N. Rahman

    (Faculty of Health and Medical Sciences, University of Copenhagen)

  • Alpay B. Seven

    (Stanford University School of Medicine
    Stanford University School of Medicine)

  • Chensong Zhang

    (Stanford University School of Medicine
    Stanford University School of Medicine)

  • Justin G. Meyerowitz

    (Stanford University School of Medicine
    Stanford University School of Medicine
    Perioperative and Pain Medicine, Stanford University School of Medicine)

  • Ouliana Panova

    (Stanford University School of Medicine
    Stanford University School of Medicine)

  • Fadil M. Hannan

    (University of Oxford
    University of Oxford)

  • Rajesh V. Thakker

    (University of Oxford)

  • Hans Bräuner-Osborne

    (Faculty of Health and Medical Sciences, University of Copenhagen)

  • Jesper M. Mathiesen

    (Faculty of Health and Medical Sciences, University of Copenhagen)

  • Georgios Skiniotis

    (Stanford University School of Medicine
    Stanford University School of Medicine)

Abstract

The calcium-sensing receptor (CaSR), a cell-surface sensor for Ca2+, is the master regulator of calcium homeostasis in humans and is the target of calcimimetic drugs for the treatment of parathyroid disorders1. CaSR is a family C G-protein-coupled receptor2 that functions as an obligate homodimer, with each protomer composed of a Ca2+-binding extracellular domain and a seven-transmembrane-helix domain (7TM) that activates heterotrimeric G proteins. Here we present cryo-electron microscopy structures of near-full-length human CaSR in inactive or active states bound to Ca2+ and various calcilytic or calcimimetic drug molecules. We show that, upon activation, the CaSR homodimer adopts an asymmetric 7TM configuration that primes one protomer for G-protein coupling. This asymmetry is stabilized by 7TM-targeting calcimimetic drugs adopting distinctly different poses in the two protomers, whereas the binding of a calcilytic drug locks CaSR 7TMs in an inactive symmetric configuration. These results provide a detailed structural framework for CaSR activation and the rational design of therapeutics targeting this receptor.

Suggested Citation

  • Yang Gao & Michael J. Robertson & Sabrina N. Rahman & Alpay B. Seven & Chensong Zhang & Justin G. Meyerowitz & Ouliana Panova & Fadil M. Hannan & Rajesh V. Thakker & Hans Bräuner-Osborne & Jesper M. M, 2021. "Asymmetric activation of the calcium-sensing receptor homodimer," Nature, Nature, vol. 595(7867), pages 455-459, July.
    • Handle: RePEc:nat:nature:v:595:y:2021:i:7867:d:10.1038_s41586-021-03691-0
    DOI: 10.1038/s41586-021-03691-0
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41586-021-03691-0
    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/s41586-021-03691-0?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. Pengfei Yan & Xi Lin & Lijie Wu & Lu Xu & Fei Li & Junlin Liu & Fei Xu, 2024. "The binding mechanism of an anti-multiple myeloma antibody to the human GPRC5D homodimer," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    2. Janik B. Hedderich & Margherita Persechino & Katharina Becker & Franziska M. Heydenreich & Torben Gutermuth & Michel Bouvier & Moritz Bünemann & Peter Kolb, 2022. "The pocketome of G-protein-coupled receptors reveals previously untargeted allosteric sites," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    3. Alexa Strauss & Alberto J. Gonzalez-Hernandez & Joon Lee & Nohely Abreu & Purushotham Selvakumar & Leslie Salas-Estrada & Melanie Kristt & Anisul Arefin & Kevin Huynh & Dagan C. Marx & Kristen Gillila, 2024. "Structural basis of positive allosteric modulation of metabotropic glutamate receptor activation and internalization," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    4. Yaejin Yun & Hyeongseop Jeong & Thibaut Laboute & Kirill A. Martemyanov & Hyung Ho Lee, 2024. "Cryo-EM structure of human class C orphan GPCR GPR179 involved in visual processing," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    5. Michael R. Schamber & Reza Vafabakhsh, 2022. "Mechanism of sensitivity modulation in the calcium-sensing receptor via electrostatic tuning," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    6. Xin Lin & Davide Provasi & Colleen M. Niswender & Wesley B. Asher & Jonathan A. Javitch, 2024. "Elucidating the molecular logic of a metabotropic glutamate receptor heterodimer," 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:595:y:2021:i:7867:d:10.1038_s41586-021-03691-0. 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.