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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 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.

Authors:
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Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
AHANIGMS
OSTI Identifier:
1306614
Resource Type:
Journal Article
Journal Name:
eLife
Additional Journal Information:
Journal Volume: 5; Journal Issue: 2016; Journal ID: ISSN 2050-084X
Publisher:
eLife Sciences Publications, Ltd.
Country of Publication:
United States
Language:
ENGLISH

Citation Formats

Geng, Yong, Mosyak, Lidia, Kurinov, Igor, Zuo, Hao, Sturchler, Emmanuel, Cheng, Tat Cheung, Subramanyam, Prakash, Brown, Alice P., Brennan, Sarah C., Mun, Hee-chang, Bush, Martin, Chen, Yan, Nguyen, Trang X., Cao, Baohua, Chang, Donald D., Quick, Matthias, Conigrave, Arthur D., Colecraft, Henry M., McDonald, Patricia, and Fan, Qing R. Structural mechanism of ligand activation in human calcium-sensing receptor. United States: N. p., 2016. Web. doi:10.7554/eLife.13662.
Geng, Yong, Mosyak, Lidia, Kurinov, Igor, Zuo, Hao, Sturchler, Emmanuel, Cheng, Tat Cheung, Subramanyam, Prakash, Brown, Alice P., Brennan, Sarah C., Mun, Hee-chang, Bush, Martin, Chen, Yan, Nguyen, Trang X., Cao, Baohua, Chang, Donald D., Quick, Matthias, Conigrave, Arthur D., Colecraft, Henry M., McDonald, Patricia, & Fan, Qing R. Structural mechanism of ligand activation in human calcium-sensing receptor. United States. https://doi.org/10.7554/eLife.13662
Geng, Yong, Mosyak, Lidia, Kurinov, Igor, Zuo, Hao, Sturchler, Emmanuel, Cheng, Tat Cheung, Subramanyam, Prakash, Brown, Alice P., Brennan, Sarah C., Mun, Hee-chang, Bush, Martin, Chen, Yan, Nguyen, Trang X., Cao, Baohua, Chang, Donald D., Quick, Matthias, Conigrave, Arthur D., Colecraft, Henry M., McDonald, Patricia, and Fan, Qing R. 2016. "Structural mechanism of ligand activation in human calcium-sensing receptor". United States. https://doi.org/10.7554/eLife.13662.
@article{osti_1306614,
title = {Structural mechanism of ligand activation in human calcium-sensing receptor},
author = {Geng, Yong and Mosyak, Lidia and Kurinov, Igor and Zuo, Hao and Sturchler, Emmanuel and Cheng, Tat Cheung and Subramanyam, Prakash and Brown, Alice P. and Brennan, Sarah C. and Mun, Hee-chang and Bush, Martin and Chen, Yan and Nguyen, Trang X. and Cao, Baohua and Chang, Donald D. and Quick, Matthias and Conigrave, Arthur D. and Colecraft, Henry M. and McDonald, Patricia and Fan, Qing R.},
abstractNote = {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.},
doi = {10.7554/eLife.13662},
url = {https://www.osti.gov/biblio/1306614}, journal = {eLife},
issn = {2050-084X},
number = 2016,
volume = 5,
place = {United States},
year = {Tue Jul 19 00:00:00 EDT 2016},
month = {Tue Jul 19 00:00:00 EDT 2016}
}