气候变化领域集成服务门户(CCPortal): Symmetric activation and modulation of the human calcium-sensing receptor

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DOI	10.1073/pnas.2115849118
	Symmetric activation and modulation of the human calcium-sensing receptor
	Park J.; Zuo H.; Frangaj A.; Fu Z.; Yen L.Y.; Zhang Z.; Mosyak L.; Slavkovich V.N.; Liu J.; Ray K.M.; Cao B.; Vallese F.; Geng Y.; Chen S.; Grassucci R.; Dandey V.P.; Tan Y.Z.; Eng E.; Lee Y.; Kloss B.; Liu Z.; Hendrickson W.A.; Potter C.S.; Carragher B.; Graziano J.; Conigrave A.D.; Frank J.; Clarke O.B.; Fan Q.R.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:51
英文摘要	The human extracellular calcium-sensing (CaS) receptor controls plasma Ca2+ levels and contributes to nutrient-dependent maintenance and metabolism of diverse organs. Allosteric modulation of the CaS receptor corrects disorders of calcium homeostasis. Here, we report the cryogenic-electron microscopy reconstructions of a near–full-length CaS receptor in the absence and presence of allosteric modulators. Activation of the homodimeric CaS receptor requires a break in the transmembrane 6 (TM6) helix of each subunit, which facilitates the formation of a TM6-mediated homodimer interface and expansion of homodimer interactions. This transformation in TM6 occurs without a positive allosteric modulator. Two modulators with opposite functional roles bind to overlapping sites within the transmembrane domain through common interactions, acting to stabilize distinct rotamer conformations of key residues on the TM6 helix. The positive modulator reinforces TM6 distortion and maximizes subunit contact to enhance receptor activity, while the negative modulator strengthens an intact TM6 to dampen receptor function. In both active and inactive states, the receptor displays symmetrical transmembrane conformations that are consistent with its homodimeric assembly. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Activation mechanism; Allosteric modulation; Calcium-sensing receptor; Cryo-EM structure; Symmetry
语种	英语
scopus关键词	calcium; calcium sensing receptor; cryoelectron microscopy; gene expression regulation; genetics; HEK293 cell line; homeostasis; human; metabolism; molecular model; physiology; protein conformation; protein domain; signal transduction; Calcium; Cryoelectron Microscopy; Gene Expression Regulation; HEK293 Cells; Homeostasis; Humans; Models, Molecular; Protein Conformation; Protein Domains; Receptors, Calcium-Sensing; Signal Transduction
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/250907
作者单位	Department of Pharmacology, Columbia University, New York, NY 10032, United States; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, United States; National Resource for Automated Molecular Microscopy, Simons Electron Microscopy Center, New York Structural Biology Center, New York, NY 10027, United States; Department of Environmental Health Sciences, Columbia University, New York, NY 10032, United States; Department of Anesthesiology, Columbia University, New York, NY 10032, United States; Irving Institute for Clinical and Translational Research, Columbia University, New York, NY 10032, United States; Medical Research Council Laboratory of Molecular Biology, Cambridge, CB2 0QH, United Kingdom; Department of Physiology and Cellular Biophysics, Columbia University, New York, NY 10032, United States; Department of Biological Sciences, National University of Singapore119077, Singapore; Disease Intervention Technology Laboratory, Agency for Science, Technolog...
推荐引用方式 GB/T 7714	Park J.,Zuo H.,Frangaj A.,et al. Symmetric activation and modulation of the human calcium-sensing receptor[J],2021,118(51).
APA	Park J..,Zuo H..,Frangaj A..,Fu Z..,Yen L.Y..,...&Fan Q.R..(2021).Symmetric activation and modulation of the human calcium-sensing receptor.Proceedings of the National Academy of Sciences of the United States of America,118(51).
MLA	Park J.,et al."Symmetric activation and modulation of the human calcium-sensing receptor".Proceedings of the National Academy of Sciences of the United States of America 118.51(2021).