Structures of the glucocorticoid-bound adhesion receptor GPR97–Go complex

• Published in: Nature (London) Vol. 589; no. 7843; pp. 620 - 626
• Main Authors: Ping, Yu-Qi, Mao, Chunyou, Xiao, Peng, Zhao, Ru-Jia, Jiang, Yi, Yang, Zhao, An, Wen-Tao, Shen, Dan-Dan, Yang, Fan, Zhang, Huibing, Qu, Changxiu, Shen, Qingya, Tian, Caiping, Li, Zi-jian, Li, Shaolong, Wang, Guang-Yu, Tao, Xiaona, Wen, Xin, Zhong, Ya-Ni, Yang, Jing, Yi, Fan, Yu, Xiao, Xu, H. Eric, Zhang, Yan, Sun, Jin-Peng
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 28.01.2021; Nature Publishing Group
• Subjects: 101/28; 631/45/535/1258/1259; 631/535/1258/1259; Adhesion; Anti-inflammatory agents; Binding; Cortisol; Coupling; Domains; Electron microscopy; G protein-coupled receptors; Glucocorticoids; Hormones; Humanities and Social Sciences; Hypotheses; Inflammation; Ligands; Microscopy; multidisciplinary; Palmitoylation; Proteins; Receptors; Science; Science (multidisciplinary); Steroids
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-020-03083-w

Adhesion G-protein-coupled receptors (GPCRs) are a major family of GPCRs, but limited knowledge of their ligand regulation or structure is available 1 – 3 . Here we report that glucocorticoid stress hormones activate adhesion G-protein-coupled receptor G3 (ADGRG3; also known as GPR97) 4 – 6 , a prototypical adhesion GPCR. The cryo-electron microscopy structures of GPR97–G o complexes bound to the anti-inflammatory drug beclomethasone or the steroid hormone cortisol revealed that glucocorticoids bind to a pocket within the transmembrane domain. The steroidal core of glucocorticoids is packed against the ‘toggle switch’ residue W 6.53 , which senses the binding of a ligand and induces activation of the receptor. Active GPR97 uses a quaternary core and HLY motif to fasten the seven-transmembrane bundle and to mediate G protein coupling. The cytoplasmic side of GPR97 has an open cavity, where all three intracellular loops interact with the G o protein, contributing to the high basal activity of GRP97. Palmitoylation at the cytosolic tail of the G o protein was found to be essential for efficient engagement with GPR97 but is not observed in other solved GPCR complex structures. Our work provides a structural basis for ligand binding to the seven-transmembrane domain of an adhesion GPCR and subsequent G protein coupling. The authors report on the structure of a glucocorticoid-bound adhesion G-protein-coupled receptor–G protein complex.