Please use this identifier to cite or link to this item: https://doi.org/10.1073/pnas.2115849118
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dc.titleSymmetric activation and modulation of the human calcium-sensing receptor
dc.contributor.authorPark, J
dc.contributor.authorZuo, H
dc.contributor.authorFrangaj, A
dc.contributor.authorFu, Z
dc.contributor.authorYen, LY
dc.contributor.authorZhang, Z
dc.contributor.authorMosyak, L
dc.contributor.authorSlavkovich, VN
dc.contributor.authorLiu, J
dc.contributor.authorRay, KM
dc.contributor.authorCao, B
dc.contributor.authorVallese, F
dc.contributor.authorGeng, Y
dc.contributor.authorChen, S
dc.contributor.authorGrassucci, R
dc.contributor.authorDandey, VP
dc.contributor.authorTan, YZ
dc.contributor.authorEng, E
dc.contributor.authorLee, Y
dc.contributor.authorKloss, B
dc.contributor.authorLiu, Z
dc.contributor.authorHendrickson, WA
dc.contributor.authorPotter, CS
dc.contributor.authorCarragher, B
dc.contributor.authorGraziano, J
dc.contributor.authorConigrave, AD
dc.contributor.authorFrank, J
dc.contributor.authorClarke, OB
dc.contributor.authorFan, QR
dc.date.accessioned2022-06-20T02:01:35Z
dc.date.available2022-06-20T02:01:35Z
dc.date.issued2021-12-21
dc.identifier.citationPark, J, Zuo, H, Frangaj, A, Fu, Z, Yen, LY, Zhang, Z, Mosyak, L, Slavkovich, VN, Liu, J, Ray, KM, Cao, B, Vallese, F, Geng, Y, Chen, S, Grassucci, R, Dandey, VP, Tan, YZ, Eng, E, Lee, Y, Kloss, B, Liu, Z, Hendrickson, WA, Potter, CS, Carragher, B, Graziano, J, Conigrave, AD, Frank, J, Clarke, OB, Fan, QR (2021-12-21). 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) : e2115849118-. ScholarBank@NUS Repository. https://doi.org/10.1073/pnas.2115849118
dc.identifier.issn00278424
dc.identifier.issn10916490
dc.identifier.urihttps://scholarbank.nus.edu.sg/handle/10635/227196
dc.description.abstractThe 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.
dc.publisherProceedings of the National Academy of Sciences
dc.sourceElements
dc.subjectactivation mechanism
dc.subjectallosteric modulation
dc.subjectcalcium-sensing receptor
dc.subjectcryo-EM structure
dc.subjectsymmetry
dc.subjectCalcium
dc.subjectCryoelectron Microscopy
dc.subjectGene Expression Regulation
dc.subjectHEK293 Cells
dc.subjectHomeostasis
dc.subjectHumans
dc.subjectModels, Molecular
dc.subjectProtein Conformation
dc.subjectProtein Domains
dc.subjectReceptors, Calcium-Sensing
dc.subjectSignal Transduction
dc.typeArticle
dc.date.updated2022-06-18T14:48:59Z
dc.contributor.departmentDEPT OF BIOLOGICAL SCIENCES
dc.description.doi10.1073/pnas.2115849118
dc.description.sourcetitleProceedings of the National Academy of Sciences of the United States of America
dc.description.volume118
dc.description.issue51
dc.description.pagee2115849118-
dc.published.statePublished
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