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https://doi.org/10.1073/pnas.2115849118
Title: | Symmetric activation and modulation of the human calcium-sensing receptor | Authors: | Park, 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 |
Keywords: | activation mechanism allosteric modulation calcium-sensing receptor cryo-EM structure symmetry Calcium Cryoelectron Microscopy Gene Expression Regulation HEK293 Cells Homeostasis Humans Models, Molecular Protein Conformation Protein Domains Receptors, Calcium-Sensing Signal Transduction |
Issue Date: | 21-Dec-2021 | Publisher: | Proceedings of the National Academy of Sciences | Citation: | Park, 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 | Abstract: | 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. | Source Title: | Proceedings of the National Academy of Sciences of the United States of America | URI: | https://scholarbank.nus.edu.sg/handle/10635/227196 | ISSN: | 00278424 10916490 |
DOI: | 10.1073/pnas.2115849118 |
Appears in Collections: | Staff Publications Elements |
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