TY - JOUR

T1 - Asymmetric activation of the calcium-sensing receptor homodimer

AU - Gao, Yang

AU - Robertson, Michael J.

AU - Rahman, Sabrina N.

AU - Seven, Alpay B.

AU - Zhang, Chensong

AU - Meyerowitz, Justin G.

AU - Panova, Ouliana

AU - Hannan, Fadil M.

AU - Thakker, Rajesh V.

AU - Bräuner-Osborne, Hans

AU - Mathiesen, Jesper M.

AU - Skiniotis, Georgios

N1 - Funding Information: Acknowledgements We thank E. Montabana at the Stanford-SLAC cryo-EM facility for support with data collection and B. Kobilka for comments on the manuscript. This work was supported, in part, by R01 NS092695 (G.S. and J.M.M.) and a grant from the Mathers Foundation (G.S.); a Wellcome Trust Investigator Award (grant number 106995/Z/15/Z) (R.V.T); National Institute for Health Research (NIHR) Oxford Biomedical Research Centre Programme (R.V.T.); NIHR Senior Investigator Award (R.V.T.) (grant number NF-SI-0514–10091); T32-GM089626 (J.G.M.); and funding from the Faculty of Health and Medical Sciences (H.B.-O.). Publisher Copyright: © 2021, The Author(s), under exclusive licence to Springer Nature Limited.

PY - 2021

Y1 - 2021

N2 - 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.

AB - 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.

U2 - 10.1038/s41586-021-03691-0

DO - 10.1038/s41586-021-03691-0

M3 - Journal article

C2 - 34194040

AN - SCOPUS:85108916552

VL - 595

SP - 455

EP - 459

JO - Nature

JF - Nature

SN - 0028-0836

ER -