Structural insights into the activation of human calcium-sensing receptor

• DOI: 10.7554/elife.68578
• Publication Date: 2021-09-01T12:00:37Z
• Authors: Xiaochen Chen; Lu Wang; Qianqian Cui; Zhanyu Ding; Li Han; Yongjun Kou; Wenqing Zhang; Haonan Wang; Xiaomin Jia; Mei Dai; Zhenzhong Shi; Yuying Li; Xiyang Li; Yong Geng
• Keywords: calcium ions; Models, Molecular; G-protein-coupled receptor; calcium-sensing receptor; QH301-705.5; Protein Conformation; Science; Structural Biology and Molecular Biophysics; Q; Cryoelectron Microscopy; R; Tryptophan; cryo-electron microscopy; nanobody; CaSR; Medicine; Homeostasis; Humans; Calcium; Biology (General); Dimerization; Receptors, Calcium-Sensing; Protein Binding; Signal Transduction

Human calcium-sensing receptor (CaSR) is a G-protein-coupled receptor that maintains Ca2+ homeostasis in serum. Here, we present the cryo-electron microscopy structures of the CaSR in the inactive and agonist+PAM bound states. Complemented with previously reported structures of CaSR, we show that in addition to the full inactive and active states, there are multiple intermediate states during the activation of CaSR. We used a negative allosteric nanobody to stabilize the CaSR in the fully inactive state and found a new binding site for Ca2+ ion that acts as a composite agonist with L-amino acid to stabilize the closure of active Venus flytraps. Our data show that agonist binding leads to compaction of the dimer, proximity of the cysteine-rich domains, large-scale transitions of seven-transmembrane domains, and inter- and intrasubunit conformational changes of seven-transmembrane domains to accommodate downstream transducers. Our results reveal the structural basis for activation mechanisms of CaSR and clarify the mode of action of Ca2+ ions and L-amino acid leading to the activation of the receptor.