Asymmetric activation of the calcium-sensing receptor homodimer
<p>The calcium-sensing receptor (CaSR), a cell-surface sensor for Ca<sup>2+</sup>, is the master regulator of calcium homeostasis in humans and is the target of calcimimetic drugs for the treatment of parathyroid disorders<sup>1</sup>. CaSR is a family C G-protein-coupl...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Springer Nature
2021
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| _version_ | 1797106349083983872 |
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| author | Gao, Y Robertson, MJ Rahman, SN Seven, AB Zhang, C Meyerowitz, JG Panova, O Hannan, FM Thakker, RV Bräuner-Osborne, H Mathiesen, JM Skiniotis, G |
| author_facet | Gao, Y Robertson, MJ Rahman, SN Seven, AB Zhang, C Meyerowitz, JG Panova, O Hannan, FM Thakker, RV Bräuner-Osborne, H Mathiesen, JM Skiniotis, G |
| author_sort | Gao, Y |
| collection | OXFORD |
| description | <p>The calcium-sensing receptor (CaSR), a cell-surface sensor for Ca<sup>2+</sup>, is the master regulator of calcium homeostasis in humans and is the target of calcimimetic drugs for the treatment of parathyroid disorders<sup>1</sup>. CaSR is a family C G-protein-coupled receptor<sup>2</sup> that functions as an obligate homodimer, with each protomer composed of a Ca<sup>2+</sup>-binding extracellular domain and a seven-transmembrane-helix domain (7TM) that activates heterotrimeric G proteins. Here we present cryo-electron microscopy structures of near-full-length human CaSR in inactive or active states bound to Ca<sup>2+</sup> and various calcilytic or calcimimetic drug molecules. We show that, upon activation, the CaSR homodimer adopts an asymmetric 7TM configuration that primes one protomer for G-protein coupling. This asymmetry is stabilized by 7TM-targeting calcimimetic drugs adopting distinctly different poses in the two protomers, whereas the binding of a calcilytic drug locks CaSR 7TMs in an inactive symmetric configuration. These results provide a detailed structural framework for CaSR activation and the rational design of therapeutics targeting this receptor.</p> |
| first_indexed | 2024-03-07T07:01:24Z |
| format | Journal article |
| id | oxford-uuid:6e7ae25a-1ba1-481e-9597-baf8358fcfc7 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:01:24Z |
| publishDate | 2021 |
| publisher | Springer Nature |
| record_format | dspace |
| spelling | oxford-uuid:6e7ae25a-1ba1-481e-9597-baf8358fcfc72022-03-28T09:10:10ZAsymmetric activation of the calcium-sensing receptor homodimerJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:6e7ae25a-1ba1-481e-9597-baf8358fcfc7EnglishSymplectic ElementsSpringer Nature2021Gao, YRobertson, MJRahman, SNSeven, ABZhang, CMeyerowitz, JGPanova, OHannan, FMThakker, RVBräuner-Osborne, HMathiesen, JMSkiniotis, G<p>The calcium-sensing receptor (CaSR), a cell-surface sensor for Ca<sup>2+</sup>, is the master regulator of calcium homeostasis in humans and is the target of calcimimetic drugs for the treatment of parathyroid disorders<sup>1</sup>. CaSR is a family C G-protein-coupled receptor<sup>2</sup> that functions as an obligate homodimer, with each protomer composed of a Ca<sup>2+</sup>-binding extracellular domain and a seven-transmembrane-helix domain (7TM) that activates heterotrimeric G proteins. Here we present cryo-electron microscopy structures of near-full-length human CaSR in inactive or active states bound to Ca<sup>2+</sup> and various calcilytic or calcimimetic drug molecules. We show that, upon activation, the CaSR homodimer adopts an asymmetric 7TM configuration that primes one protomer for G-protein coupling. This asymmetry is stabilized by 7TM-targeting calcimimetic drugs adopting distinctly different poses in the two protomers, whereas the binding of a calcilytic drug locks CaSR 7TMs in an inactive symmetric configuration. These results provide a detailed structural framework for CaSR activation and the rational design of therapeutics targeting this receptor.</p> |
| spellingShingle | Gao, Y Robertson, MJ Rahman, SN Seven, AB Zhang, C Meyerowitz, JG Panova, O Hannan, FM Thakker, RV Bräuner-Osborne, H Mathiesen, JM Skiniotis, G Asymmetric activation of the calcium-sensing receptor homodimer |
| title | Asymmetric activation of the calcium-sensing receptor homodimer |
| title_full | Asymmetric activation of the calcium-sensing receptor homodimer |
| title_fullStr | Asymmetric activation of the calcium-sensing receptor homodimer |
| title_full_unstemmed | Asymmetric activation of the calcium-sensing receptor homodimer |
| title_short | Asymmetric activation of the calcium-sensing receptor homodimer |
| title_sort | asymmetric activation of the calcium sensing receptor homodimer |
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