PMID: 27434672

 

    Legend: Sugar

Title : Structural mechanism of ligand activation in human calcium-sensing receptor

Abstract :
  1. 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
  2. It functions as a disulfide-tethered homodimer composed of three main domains , the Venus Flytrap module, cysteine-rich domain , and seven-helix transmembrane region
  3. Here, we present the crystal structures of the entire extracellular domain of CaSR in the resting and active conformations
  4. We provide direct evidence that L-amino acids are agonists of the receptor
  5. 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
  6. Our structures reveal multiple binding sites for Ca(2 +) and PO4(3-) ions
  7. Both ions are crucial for structural integrity of the receptor
  8. While Ca(2 +) ions stabilize the active state, PO4(3-) ions reinforce the inactive conformation
  9. The activation mechanism of CaSR involves the formation of a novel dimer interface between subunits