Structural mechanism of ligand activation in human calcium-sensing receptor

Elife. 2016 Jul 19:5:e13662. doi: 10.7554/eLife.13662.


Human calcium-sensing receptor (CaSR) is a G-protein-coupled receptor (GPCR) that maintains extracellular Ca(2+) 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 Ca(2+) and PO4(3-) ions. Both ions are crucial for structural integrity of the receptor. While Ca(2+) ions stabilize the active state, PO4(3-) ions reinforce the inactive conformation. The activation mechanism of CaSR involves the formation of a novel dimer interface between subunits.

Keywords: amino acids; biochemistry; biophysics; calcium-sensing receptor; extracellular calcium homeostasis; extracellular domain structure; human; principal agonist; receptor activation mechanism; structural biology.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Binding Sites
  • Calcium / metabolism*
  • Crystallography, X-Ray
  • Humans
  • Models, Molecular
  • Phosphates / metabolism
  • Protein Binding
  • Protein Conformation
  • Protein Multimerization
  • Receptors, Calcium-Sensing / agonists*
  • Receptors, Calcium-Sensing / chemistry*
  • Tryptophan / chemistry*
  • Tryptophan / metabolism*


  • Phosphates
  • Receptors, Calcium-Sensing
  • Tryptophan
  • Calcium