7m3e Citations

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.

Reviews - 7m3e mentioned but not cited (1)

  1. G protein-coupled receptors in neurodegenerative diseases and psychiatric disorders. Wong TS, Li G, Li S, Gao W, Chen G, Gan S, Zhang M, Li H, Wu S, Du Y. Signal Transduct Target Ther 8 177 (2023)

Articles - 7m3e mentioned but not cited (3)



Reviews citing this publication (6)

  1. Class A and C GPCR Dimers in Neurodegenerative Diseases. Caniceiro AB, Bueschbell B, Schiedel AC, Moreira IS. Curr Neuropharmacol 20 2081-2141 (2022)
  2. Allosteric modulation of G protein-coupled receptor signaling. Shen S, Zhao C, Wu C, Sun S, Li Z, Yan W, Shao Z. Front Endocrinol (Lausanne) 14 1137604 (2023)
  3. Calcium-Sensing Receptor (CaSR)-Mediated Intracellular Communication in Cardiovascular Diseases. Chu H, Qin Z, Ma J, Xie Y, Shi H, Gu J, Shi B. Cells 11 3075 (2022)
  4. Extracellular Calcium Receptor as a Target for Glutathione and Its Derivatives. Goralski T, Ram JL. Int J Mol Sci 23 717 (2022)
  5. Inhibition of the calcium-sensing receptor by extracellular phosphate ions and by intracellular phosphorylation. Centeno PP, Binmahfouz LS, Alghamdi K, Ward DT. Front Physiol 14 1154374 (2023)
  6. Structure, function and drug discovery of GPCR signaling. Cheng L, Xia F, Li Z, Shen C, Yang Z, Hou H, Sun S, Feng Y, Yong X, Tian X, Qin H, Yan W, Shao Z. Mol Biomed 4 46 (2023)

Articles citing this publication (17)