Structural mechanism of ligand activation in human calcium-sensing receptor
- Columbia University, United States
- Cornell University, United States
- The Scripps Translational Science Institute, United States
- University of Sydney, Australia
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.
Data availability
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Crystal structure of the inactive form of human calcium-sensing receptor extracellular domainPublicly available at the RCSB Protein Data Bank (accession no: 5K5T).
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Crystal structure of the active form of human calcium-sensing receptor extracellular domainPublicly available at the RCSB Protein Data Bank (accession no: 5K5S).
Article and author information
Author details
Funding
National Institute of General Medical Sciences (R01GM112973)
- Qing R Fan
American Heart Association (15GRNT25420002)
- Qing R Fan
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2016, Geng et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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