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