5K5T: Crystal Structure Of The Inactive Form Of Human Calcium-sensing Receptor Extracellular Domain

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.
PDB ID: 5K5TDownload
MMDB ID: 141588
PDB Deposition Date: 2016/5/23
Updated in MMDB: 2017/10
Experimental Method:
x-ray diffraction
Resolution: 3.1  Å
Source Organism:
Similar Structures:
Biological Unit for 5K5T: dimeric; determined by author and by software (PISA)
Molecular Components in 5K5T
Label Count Molecule
Proteins (2 molecules)
Extracellular Calcium-sensing Receptor(Gene symbol: CASR)
Molecule annotation
Chemicals (22 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB