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

Yu-Qi Ping, Chunyou Mao, Peng Xiao, Ru-Jia Zhao, Yi Jiang, Zhao Yang, Wen-Tao An, Dan-Dan Shen, Fan Yang, Huibing Zhang, Changxiu Qu, Qingya Shen, Caiping Tian, Zi-jian Li, Shaolong Li, Guang-Yu Wang, Xiaona Tao, Xin Wen, Ya-Ni Zhong, Jing Yang, Fan Yi, Xiao Yu, H. Eric Xu (), Yan Zhang () and Jin-Peng Sun ()
Additional contact information
Yu-Qi Ping: CAS Key Laboratory of Receptor Research, Center for Structure and Function of Drug Targets, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Chunyou Mao: Zhejiang University School of Medicine
Peng Xiao: Shandong University
Ru-Jia Zhao: Shandong University
Yi Jiang: CAS Key Laboratory of Receptor Research, Center for Structure and Function of Drug Targets, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Zhao Yang: Shandong University
Wen-Tao An: Shandong University
Dan-Dan Shen: Zhejiang University School of Medicine
Fan Yang: Shandong University
Huibing Zhang: Zhejiang University School of Medicine
Changxiu Qu: Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education
Qingya Shen: Zhejiang University School of Medicine
Caiping Tian: State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences Beijing, Beijing Institute of Lifeomics
Zi-jian Li: Peking University
Shaolong Li: Shandong University
Guang-Yu Wang: Shandong University
Xiaona Tao: Shandong University
Xin Wen: Shandong University
Ya-Ni Zhong: Shandong University
Jing Yang: State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences Beijing, Beijing Institute of Lifeomics
Fan Yi: Shandong University
Xiao Yu: Shandong University
H. Eric Xu: CAS Key Laboratory of Receptor Research, Center for Structure and Function of Drug Targets, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Yan Zhang: Zhejiang University School of Medicine
Jin-Peng Sun: Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education

Nature, 2021, vol. 589, issue 7843, 620-626

Abstract: Abstract Adhesion G-protein-coupled receptors (GPCRs) are a major family of GPCRs, but limited knowledge of their ligand regulation or structure is available1–3. 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–Go 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 W6.53, 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 Go protein, contributing to the high basal activity of GRP97. Palmitoylation at the cytosolic tail of the Go 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.

Date: 2021
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DOI: 10.1038/s41586-020-03083-w

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