Structural mechanism of ligand activation in human calcium-sensing receptor
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 d...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2016-07-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/13662 |
| _version_ | 1818019215091695616 |
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| author | Yong Geng Lidia Mosyak Igor Kurinov Hao Zuo Emmanuel Sturchler Tat Cheung Cheng Prakash Subramanyam Alice P Brown Sarah C Brennan Hee-chang Mun Martin Bush Yan Chen Trang X Nguyen Baohua Cao Donald D Chang Matthias Quick Arthur D Conigrave Henry M Colecraft Patricia McDonald Qing R Fan |
| author_facet | Yong Geng Lidia Mosyak Igor Kurinov Hao Zuo Emmanuel Sturchler Tat Cheung Cheng Prakash Subramanyam Alice P Brown Sarah C Brennan Hee-chang Mun Martin Bush Yan Chen Trang X Nguyen Baohua Cao Donald D Chang Matthias Quick Arthur D Conigrave Henry M Colecraft Patricia McDonald Qing R Fan |
| author_sort | Yong Geng |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-14T07:49:19Z |
| format | Article |
| id | doaj.art-e63fb37743704af49f79c4f8b8cc2622 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-14T07:49:19Z |
| publishDate | 2016-07-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-e63fb37743704af49f79c4f8b8cc26222022-12-22T02:05:15ZengeLife Sciences Publications LtdeLife2050-084X2016-07-01510.7554/eLife.13662Structural mechanism of ligand activation in human calcium-sensing receptorYong Geng0Lidia Mosyak1Igor Kurinov2Hao Zuo3Emmanuel Sturchler4Tat Cheung Cheng5Prakash Subramanyam6Alice P Brown7Sarah C Brennan8Hee-chang Mun9Martin Bush10Yan Chen11Trang X Nguyen12Baohua Cao13Donald D Chang14Matthias Quick15Arthur D Conigrave16Henry M Colecraft17Patricia McDonald18Qing R Fan19https://orcid.org/0000-0002-9330-0963Department of Pharmacology, Columbia University, New York, United States; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, ChinaDepartment of Pharmacology, Columbia University, New York, United StatesDepartment of Chemistry and Chemical Biology, Cornell University, Ithaca, United StatesDepartment of Pharmacology, Columbia University, New York, United StatesDepartment of Molecular Therapeutics, The Scripps Translational Science Institute, Jupiter, United StatesDepartment of Pharmacology, Columbia University, New York, United StatesDepartment of Physiology and Cellular Biophysics, Columbia University, New York, United StatesSchool of Life and Environmental Sciences, University of Sydney, New South Wales, AustraliaSchool of Life and Environmental Sciences, University of Sydney, New South Wales, AustraliaSchool of Life and Environmental Sciences, University of Sydney, New South Wales, AustraliaDepartment of Pharmacology, Columbia University, New York, United StatesDepartment of Pharmacology, Columbia University, New York, United StatesDepartment of Psychiatry, Columbia University, New York, United StatesDepartment of Pharmacology, Columbia University, New York, United StatesDepartment of Physiology and Cellular Biophysics, Columbia University, New York, United StatesDepartment of Psychiatry, Columbia University, New York, United StatesSchool of Life and Environmental Sciences, University of Sydney, New South Wales, AustraliaDepartment of Physiology and Cellular Biophysics, Columbia University, New York, United StatesDepartment of Molecular Therapeutics, The Scripps Translational Science Institute, Jupiter, United StatesDepartment of Pharmacology, Columbia University, New York, United States; Department of Pathology and Cell Biology, Columbia University, New York, United StatesHuman 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.https://elifesciences.org/articles/13662calcium-sensing receptorextracellular calcium homeostasisprincipal agonistamino acidsextracellular domain structurereceptor activation mechanism |
| spellingShingle | Yong Geng Lidia Mosyak Igor Kurinov Hao Zuo Emmanuel Sturchler Tat Cheung Cheng Prakash Subramanyam Alice P Brown Sarah C Brennan Hee-chang Mun Martin Bush Yan Chen Trang X Nguyen Baohua Cao Donald D Chang Matthias Quick Arthur D Conigrave Henry M Colecraft Patricia McDonald Qing R Fan Structural mechanism of ligand activation in human calcium-sensing receptor eLife calcium-sensing receptor extracellular calcium homeostasis principal agonist amino acids extracellular domain structure receptor activation mechanism |
| title | Structural mechanism of ligand activation in human calcium-sensing receptor |
| title_full | Structural mechanism of ligand activation in human calcium-sensing receptor |
| title_fullStr | Structural mechanism of ligand activation in human calcium-sensing receptor |
| title_full_unstemmed | Structural mechanism of ligand activation in human calcium-sensing receptor |
| title_short | Structural mechanism of ligand activation in human calcium-sensing receptor |
| title_sort | structural mechanism of ligand activation in human calcium sensing receptor |
| topic | calcium-sensing receptor extracellular calcium homeostasis principal agonist amino acids extracellular domain structure receptor activation mechanism |
| url | https://elifesciences.org/articles/13662 |
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