Back to Search
Start Over
Structural mechanism of ligand activation in human calcium-sensing receptor
- Source :
- eLife, Vol 5 (2016)
- Publication Year :
- 2016
- Publisher :
- eLife Sciences Publications Ltd, 2016.
-
Abstract
- 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.
Details
- Language :
- English
- ISSN :
- 2050084X
- Volume :
- 5
- Database :
- Directory of Open Access Journals
- Journal :
- eLife
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.63fb37743704af49f79c4f8b8cc2622
- Document Type :
- article
- Full Text :
- https://doi.org/10.7554/eLife.13662