Asymmetric activation of the calcium-sensing receptor homodimer

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. Mathiesen () and Georgios Skiniotis ()
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Yang Gao: Stanford University School of Medicine
Michael J. Robertson: 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
Chensong Zhang: Stanford University School of Medicine
Justin G. Meyerowitz: Stanford University School of Medicine
Ouliana Panova: Stanford University School of Medicine
Fadil M. Hannan: 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

Nature, 2021, vol. 595, issue 7867, 455-459

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41586-021-03691-0

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