Structures of the glucocorticoid-bound adhesion receptor GPR97-G o complex

Adhesion G-protein-coupled receptors (GPCRs) are a major family of GPCRs, but limited knowledge of their ligand regulation or structure is available . Here we report that glucocorticoid stress hormones activate adhesion G-protein-coupled receptor G3 (ADGRG3; also known as GPR97) , a prototypical adh...

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Published in:Nature (London) 2021-01, Vol.589 (7843), p.620
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: Article
Language:English
Subjects:
Binding Sites
Cryoelectron Microscopy
Glucocorticoids - chemistry
Glucocorticoids - metabolism
GTP-Binding Protein alpha Subunits, Gi-Go - chemistry
GTP-Binding Protein alpha Subunits, Gi-Go - metabolism
GTP-Binding Protein alpha Subunits, Gi-Go - ultrastructure
Humans
Ligands
Lipoylation
Models, Molecular
Protein Binding
Receptors, G-Protein-Coupled - chemistry
Receptors, G-Protein-Coupled - metabolism
Receptors, G-Protein-Coupled - ultrastructure
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Summary:Adhesion G-protein-coupled receptors (GPCRs) are a major family of GPCRs, but limited knowledge of their ligand regulation or structure is available . Here we report that glucocorticoid stress hormones activate adhesion G-protein-coupled receptor G3 (ADGRG3; also known as GPR97) , a prototypical adhesion GPCR. The cryo-electron microscopy structures of GPR97-G 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 , 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 protein, contributing to the high basal activity of GRP97. Palmitoylation at the cytosolic tail of the G 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.
ISSN:1476-4687