eLife (Jul 2016)

Structural mechanism of ligand activation in human calcium-sensing receptor

  • Yong Geng,
  • Lidia Mosyak,
  • Igor Kurinov,
  • Hao Zuo,
  • Emmanuel Sturchler,
  • Tat Cheung Cheng,
  • Prakash Subramanyam,
  • Alice P Brown,
  • Sarah C Brennan,
  • Hee-chang Mun,
  • Martin Bush,
  • Yan Chen,
  • Trang X Nguyen,
  • Baohua Cao,
  • Donald D Chang,
  • Matthias Quick,
  • Arthur D Conigrave,
  • Henry M Colecraft,
  • Patricia McDonald,
  • Qing R Fan

DOI
https://doi.org/10.7554/eLife.13662
Journal volume & issue
Vol. 5

Abstract

Read online

Human calcium-sensing receptor (CaSR) is a G-protein-coupled receptor (GPCR) that maintains extracellular Ca2+ homeostasis through the regulation of parathyroid hormone secretion. It functions as a disulfide-tethered homodimer composed of three main domains, the Venus Flytrap module, cysteine-rich domain, and seven-helix transmembrane region. Here, we present the crystal structures of the entire extracellular domain of CaSR in the resting and active conformations. We provide direct evidence that L-amino acids are agonists of the receptor. In the active structure, L-Trp occupies the orthosteric agonist-binding site at the interdomain cleft and is primarily responsible for inducing extracellular domain closure to initiate receptor activation. Our structures reveal multiple binding sites for Ca2+ and PO43- ions. Both ions are crucial for structural integrity of the receptor. While Ca2+ ions stabilize the active state, PO43- ions reinforce the inactive conformation. The activation mechanism of CaSR involves the formation of a novel dimer interface between subunits.

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