한빛사 논문
Jinseo Parka,1, Hao Zuoa,1, Aurel Frangaja,1, Ziao Fub,1, Laura Y. Yenc,1, Zhening Zhangb,1, Lidia Mosyaka, Vesna N. Slavkovichd, Jonathan Liua, Kimberly M. Raya, Baohua Caoa, Francesca Vallesee,f, Yong Genga, Shaoxia Cheng, Robert Grassuccib, Venkata P. Dandeyc, Yong Zi Tanc,h,i,j, Edward Engc, Yeji Leea, Brian Klossk, Zheng Liub, Wayne A. Hendricksonb,h,k,2, Clinton S. Potterb,c, Bridget Carragherb,c, Joseph Grazianod, Arthur D. Conigravel,2, Joachim Frankb,m,2, Oliver B. Clarkee,f,h,2, and Qing R. Fana,n,2
aDepartment of Pharmacology, Columbia University, New York, NY 10032; bDepartment of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032; cNational Resource for Automated Molecular Microscopy, Simons Electron Microscopy Center, New York Structural Biology Center, New York, NY 10027; dDepartment of Environmental Health Sciences, Columbia University, New York, NY 10032; eDepartment of Anesthesiology, Columbia University, New York, NY 10032; fIrving Institute for Clinical and Translational Research, Columbia University, New York, NY 10032; gMedical Research Council Laboratory
of Molecular Biology, Cambridge CB2 0QH, United Kingdom; hDepartment of Physiology and Cellular Biophysics, Columbia University, New York, NY 10032; iDepartment of Biological Sciences, National University of Singapore 119077, Singapore; jDisease Intervention Technology Laboratory, Agency for Science, Technology and Research (A*STAR) 119077, Singapore; kCenter on Membrane Protein Production and Analysis, New York Structural Biology Center, New York, NY 10027; lSchool of Life and Environmental Sciences, Charles Perkins Centre, University of Sydney, Camperdown, NSW 2006, Australia; mDepartment of Biological Sciences, Columbia University, New York, NY 10027; and nDepartment of Pathology and Cell Biology, Columbia University, New York, NY 10032
1J.P., H.Z., A.F., Z.F., L.Y.Y., and Z.Z. contributed equally to this work.
2To whom correspondence may be addressed.
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.
calcium-sensing receptor, cryo-EM structure, allosteric modulation, activation mechanism, symmetry
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