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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
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    Cited by:

    1. 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.
    2. 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.

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