Structural insights into the activation of human calcium-sensing receptor

Human calcium-sensing receptor (CaSR) is a G-protein-coupled receptor that maintains Ca2+ homeostasis in serum. Here, we present the cryo-electron microscopy structures of the CaSR in the inactive and agonist+PAM bound states. Complemented with previously reported structures of CaSR, we show that in...

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Autores principales:	Xiaochen Chen, Lu Wang, Qianqian Cui, Zhanyu Ding, Li Han, Yongjun Kou, Wenqing Zhang, Haonan Wang, Xiaomin Jia, Mei Dai, Zhenzhong Shi, Yuying Li, Xiyang Li, Yong Geng
Formato:	article
Lenguaje:	EN
Publicado:	eLife Sciences Publications Ltd 2021
Materias:	G-protein-coupled receptor calcium-sensing receptor cryo-electron microscopy calcium ions nanobody CaSR Medicine R Science Q Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/1a45f3b9a85b441f841a20a5de8089b4
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spelling	oai:doaj.org-article:1a45f3b9a85b441f841a20a5de8089b42021-11-25T12:31:30ZStructural insights into the activation of human calcium-sensing receptor10.7554/eLife.685782050-084Xe68578https://doaj.org/article/1a45f3b9a85b441f841a20a5de8089b42021-09-01T00:00:00Zhttps://elifesciences.org/articles/68578https://doaj.org/toc/2050-084XHuman calcium-sensing receptor (CaSR) is a G-protein-coupled receptor that maintains Ca2+ homeostasis in serum. Here, we present the cryo-electron microscopy structures of the CaSR in the inactive and agonist+PAM bound states. Complemented with previously reported structures of CaSR, we show that in addition to the full inactive and active states, there are multiple intermediate states during the activation of CaSR. We used a negative allosteric nanobody to stabilize the CaSR in the fully inactive state and found a new binding site for Ca2+ ion that acts as a composite agonist with L-amino acid to stabilize the closure of active Venus flytraps. Our data show that agonist binding leads to compaction of the dimer, proximity of the cysteine-rich domains, large-scale transitions of seven-transmembrane domains, and inter- and intrasubunit conformational changes of seven-transmembrane domains to accommodate downstream transducers. Our results reveal the structural basis for activation mechanisms of CaSR and clarify the mode of action of Ca2+ ions and L-amino acid leading to the activation of the receptor.Xiaochen ChenLu WangQianqian CuiZhanyu DingLi HanYongjun KouWenqing ZhangHaonan WangXiaomin JiaMei DaiZhenzhong ShiYuying LiXiyang LiYong GengeLife Sciences Publications LtdarticleG-protein-coupled receptorcalcium-sensing receptorcryo-electron microscopycalcium ionsnanobodyCaSRMedicineRScienceQBiology (General)QH301-705.5ENeLife, Vol 10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	G-protein-coupled receptor calcium-sensing receptor cryo-electron microscopy calcium ions nanobody CaSR Medicine R Science Q Biology (General) QH301-705.5
spellingShingle	G-protein-coupled receptor calcium-sensing receptor cryo-electron microscopy calcium ions nanobody CaSR Medicine R Science Q Biology (General) QH301-705.5 Xiaochen Chen Lu Wang Qianqian Cui Zhanyu Ding Li Han Yongjun Kou Wenqing Zhang Haonan Wang Xiaomin Jia Mei Dai Zhenzhong Shi Yuying Li Xiyang Li Yong Geng Structural insights into the activation of human calcium-sensing receptor
description	Human calcium-sensing receptor (CaSR) is a G-protein-coupled receptor that maintains Ca2+ homeostasis in serum. Here, we present the cryo-electron microscopy structures of the CaSR in the inactive and agonist+PAM bound states. Complemented with previously reported structures of CaSR, we show that in addition to the full inactive and active states, there are multiple intermediate states during the activation of CaSR. We used a negative allosteric nanobody to stabilize the CaSR in the fully inactive state and found a new binding site for Ca2+ ion that acts as a composite agonist with L-amino acid to stabilize the closure of active Venus flytraps. Our data show that agonist binding leads to compaction of the dimer, proximity of the cysteine-rich domains, large-scale transitions of seven-transmembrane domains, and inter- and intrasubunit conformational changes of seven-transmembrane domains to accommodate downstream transducers. Our results reveal the structural basis for activation mechanisms of CaSR and clarify the mode of action of Ca2+ ions and L-amino acid leading to the activation of the receptor.
format	article
author	Xiaochen Chen Lu Wang Qianqian Cui Zhanyu Ding Li Han Yongjun Kou Wenqing Zhang Haonan Wang Xiaomin Jia Mei Dai Zhenzhong Shi Yuying Li Xiyang Li Yong Geng
author_facet	Xiaochen Chen Lu Wang Qianqian Cui Zhanyu Ding Li Han Yongjun Kou Wenqing Zhang Haonan Wang Xiaomin Jia Mei Dai Zhenzhong Shi Yuying Li Xiyang Li Yong Geng
author_sort	Xiaochen Chen
title	Structural insights into the activation of human calcium-sensing receptor
title_short	Structural insights into the activation of human calcium-sensing receptor
title_full	Structural insights into the activation of human calcium-sensing receptor
title_fullStr	Structural insights into the activation of human calcium-sensing receptor
title_full_unstemmed	Structural insights into the activation of human calcium-sensing receptor
title_sort	structural insights into the activation of human calcium-sensing receptor
publisher	eLife Sciences Publications Ltd
publishDate	2021
url	https://doaj.org/article/1a45f3b9a85b441f841a20a5de8089b4
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_version_	1718413482302373888

Structural insights into the activation of human calcium-sensing receptor

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