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; Georgios Skiniotis

doi:10.1038/s41586-021-03691-0

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^*, Georgios Skiniotis^*

^*Corresponding author for this work

Molecular and Cellular Pharmacology

Research output: Contribution to journal › Journal article › Research › peer-review

86 Citations (Scopus)

23 Downloads (Pure)

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.

Original language	English
Journal	Nature
Volume	595
Pages (from-to)	455-459
ISSN	0028-0836
DOIs	https://doi.org/10.1038/s41586-021-03691-0
Publication status	Published - 2021

Bibliographical note

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.

Access to Document

10.1038/s41586-021-03691-0

FulltextAccepted author manuscript, 7.76 MB
s41586-021-03691-0Final published version, 13.1 MB

Cite this

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.

In: Nature, Vol. 595, 2021, p. 455-459.

Research output: Contribution to journal › Journal article › Research › peer-review

@article{ef49d338b81d4e1fa080d7c5d39f90d9,

title = "Asymmetric activation of the calcium-sensing receptor homodimer",

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.",

author = "Yang Gao and Robertson, {Michael J.} and Rahman, {Sabrina N.} and Seven, {Alpay B.} and Chensong Zhang and Meyerowitz, {Justin G.} and Ouliana Panova and Hannan, {Fadil M.} and Thakker, {Rajesh V.} and Hans Br{\"a}uner-Osborne and Mathiesen, {Jesper M.} and Georgios Skiniotis",

note = "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: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2021",

doi = "10.1038/s41586-021-03691-0",

language = "English",

volume = "595",

pages = "455--459",

journal = "Nature",

issn = "0028-0836",

publisher = "nature publishing group",

}

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 -