Symmetric activation and modulation of the human calcium-sensing receptor

• DOI: 10.1073/pnas.2115849118
• Publication Date: 2021-12-16T21:16:39Z
• Authors: Jinseo Park; Hao Zuo; Aurel Frangaj; Ziao Fu; Laura Y. Yen; Zhening Zhang; Lidia Mosyak; Vesna N. Slavkovich; Jonathan Liu; Kimberly M. Ray; Baohua Cao; Francesca Vallese; Yong Geng; Shaoxia Chen; Robert Grassucci; Venkata P. Dandey; Yong Zi Tan; Edward Eng; Yeji Lee; Brian Kloss; Zheng Liu; Wayne A. Hendrickson; Clinton S. Potter; Bridget Carragher; Joseph Graziano; Arthur D. Conigrave; Joachim Frank; Oliver B. Clarke; Qing R. Fan
• Keywords: Models, Molecular; 570; 0303 health sciences; allosteric modulation; calcium-sensing receptor; Protein Conformation; Cryoelectron Microscopy; Molecular; cryo-EM structure; activation mechanism; 530; 03 medical and health sciences; HEK293 Cells; Gene Expression Regulation; Protein Domains; Models; Receptors; Homeostasis; Humans; Calcium-Sensing; Calcium; Receptors, Calcium-Sensing; symmetry; Signal Transduction

Significance The human calcium-sensing receptor maintains a stable concentration of calcium in the blood. Naturally occurring mutations in the receptor are linked to calcium homeostatic disorders including hypercalcemia and hypocalcemia. Modulation of the receptor function can provide therapeutic relief of these conditions. The structures of the calcium-sensing receptor in the absence and presence of various allosteric modulators reveal the mechanism by which these modifiers up- or down-regulate receptor function. We have captured symmetric forms of the homodimeric receptor both at rest and upon stimulation and concluded that receptor activation involves a conformational change at its dimer interface. The structural details of the calcium-sensing receptor in different functional states may assist the design of new therapeutics for diseases related to calcium homeostasis.