Asymmetric activation of the calcium-sensing receptor homodimer

  • Nature. 2021 Jul;595(7867):455-459. doi: 10.1038/s41586-021-03691-0.
Yang Gao  1  2 ,  Michael J Robertson  1  2 ,  Sabrina N Rahman  3 ,  Alpay B Seven  1  2 ,  Chensong Zhang  1  2 ,  Justin G Meyerowitz  1  2  4 ,  Ouliana Panova  1  2 ,  Fadil M Hannan  5  6 ,  Rajesh V Thakker  5 ,  Hans Bräuner-Osborne  3 ,  Jesper M Mathiesen  7 ,  Georgios Skiniotis  8  9
Affiliations
  • 1. Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.
  • 2. Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA.
  • 3. Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • 4. Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA.
  • 5. Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
  • 6. Nuffield Department of Women's & Reproductive Health, University of Oxford, Oxford, UK.
  • 7. Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. [email protected].
  • 8. Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. [email protected].
  • 9. Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA. [email protected].
PMID: 34194040 DOI: 10.1038/s41586-021-03691-0
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.

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