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.
Crystal structure of the inactive form of human calcium-sensing receptor extracellular domainPublicly available at the RCSB Protein Data Bank (accession no: 5K5T).
Crystal structure of the active form of human calcium-sensing receptor extracellular domainPublicly available at the RCSB Protein Data Bank (accession no: 5K5S).
- Qing R Fan
- Qing R Fan
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
- Ehud Y Isacoff, University of California, Berkeley, United States
© 2016, Geng et al.
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