Asymmetric activation of the calcium-sensing receptor homodimer
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Asymmetric activation of the calcium-sensing receptor homodimer. / Gao, Yang; Robertson, Michael J.; Rahman, Sabrina N.; Seven, Alpay B.; Zhang, Chensong; Meyerowitz, Justin G.; Panova, Ouliana; Hannan, Fadil M.; Thakker, Rajesh V.; Bräuner-Osborne, Hans; Mathiesen, Jesper M.; Skiniotis, Georgios.
I: Nature, Bind 595, 2021, s. 455-459.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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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 -
ID: 286501200