Structural insights into the activation of human calcium-sensing receptor

doi:10.7554/eLife.68578

	Structural insights into the activation of human calcium-sensing receptor
	Chen, Xiaochen 1; Wang, Lu 1; Cui, Qianqian 1; Ding, Zhanyu 1; Han, Li 1; Kou, Yongjun 1; Zhang, Wenqing 1; Wang, Haonan 1; Jia, Xiaomin 1; Dai, Mei 1
刊名	ELIFE
	2021-09-01
卷号	10 页码:24
关键词	G-protein-coupled receptor calcium-sensing receptor cryo-electron microscopy calcium ions nanobody CaSR GPCR cryo-EM None
ISSN号	2050-084X
DOI	10.7554/eLife.68578
通讯作者	Geng, Yong(gengyong@simm.ac.cn)
英文摘要	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.
资助项目	National Natural Science Foundation of China[31670743] ; National Natural Science Foundation of China[118180359901] ; Science and Technology Commission of Shanghai Municipality[18JC1415400] ; Joint Research Fund for Overseas Chinese Scholars and Scholars in Hong Kong and Macao[81628013] ; Natural Science Foundation of Shanghai[16ZR1442900] ; Shanghai Institute of Materia Medica, Chinese Academy of Sciences[CASIMM0120164013] ; Shanghai Institute of Materia Medica, Chinese Academy of Sciences[SIMM1606YZZ-06] ; Shanghai Institute of Materia Medica, Chinese Academy of Sciences[SIMM1601KF-06] ; Shanghai Institute of Materia Medica, Chinese Academy of Sciences[55201631121116101] ; Shanghai Institute of Materia Medica, Chinese Academy of Sciences[55201631121108000] ; Shanghai Institute of Materia Medica, Chinese Academy of Sciences[5112345601] ; Shanghai Institute of Materia Medica, Chinese Academy of Sciences[2015123456005]
WOS关键词	CA2+-SENSING RECEPTOR ; ALLOSTERIC MODULATION ; GLUTAMATE ; MECHANISM ; CELLS
WOS研究方向	Life Sciences & Biomedicine - Other Topics
语种	英语
出版者	eLIFE SCIENCES PUBL LTD
WOS记录号	WOS:000703105300001
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/297469]
专题	中国科学院上海药物研究所
通讯作者	Geng, Yong
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai, Peoples R China 2.Univ Chinese Acad Sci, Beijing, Peoples R China
推荐引用方式 GB/T 7714	Chen, Xiaochen,Wang, Lu,Cui, Qianqian,et al. Structural insights into the activation of human calcium-sensing receptor[J]. ELIFE,2021,10:24.
APA	Chen, Xiaochen.,Wang, Lu.,Cui, Qianqian.,Ding, Zhanyu.,Han, Li.,...&Geng, Yong.(2021).Structural insights into the activation of human calcium-sensing receptor.ELIFE,10,24.
MLA	Chen, Xiaochen,et al."Structural insights into the activation of human calcium-sensing receptor".ELIFE 10(2021):24.