2. Academic Validation
  3. Structures of the glucocorticoid-bound adhesion receptor GPR97-Go complex

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

  • Nature. 2021 Jan;589(7843):620-626. doi: 10.1038/s41586-020-03083-w.
Yu-Qi Ping  # 1 2 3,  Chunyou Mao  # 4 5,  Peng Xiao  # 3,  Ru-Jia Zhao  # 3,  Yi Jiang  # 1,  Zhao Yang 3,  Wen-Tao An 3,  Dan-Dan Shen 4 5,  Fan Yang 3 6,  Huibing Zhang 4 5,  Changxiu Qu 2 3,  Qingya Shen 4 5,  Caiping Tian 7 8,  Zi-Jian Li 9,  Shaolong Li 3,  Guang-Yu Wang 3,  Xiaona Tao 3,  Xin Wen 3,  Ya-Ni Zhong 3,  Jing Yang 7,  Fan Yi 10,  Xiao Yu 6,  H Eric Xu 11,  Yan Zhang 12 13 14 15,  Jin-Peng Sun 16 17
Affiliations

Affiliations

  • 1 CAS Key Laboratory of Receptor Research, Center for Structure and Function of Drug Targets, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • 2 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China.
  • 3 Key Laboratory Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Shandong, China.
  • 4 Department of Biophysics, and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 5 Zhejiang Laboratory for Systems and Precision Medicine, Zhejiang University Medical Center, Hangzhou, China.
  • 6 Key Laboratory Experimental Teratology of the Ministry of Education, Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Shandong, China.
  • 7 State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences Beijing, Beijing Institute of Lifeomics, Beijing, China.
  • 8 School of Medicine, Tsinghua University, Beijing, China.
  • 9 Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University, Beijing, China.
  • 10 The Key Laboratory of Infection and Immunity of Shandong Province, Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Shandong, China.
  • 11 CAS Key Laboratory of Receptor Research, Center for Structure and Function of Drug Targets, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. eric.xu@simm.ac.cn.
  • 12 Department of Biophysics, and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China. zhang_yan@zju.edu.cn.
  • 13 Zhejiang Laboratory for Systems and Precision Medicine, Zhejiang University Medical Center, Hangzhou, China. zhang_yan@zju.edu.cn.
  • 14 Zhejiang Provincial Key Laboratory of Immunity and Inflammatory Diseases, Hangzhou, China. zhang_yan@zju.edu.cn.
  • 15 MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University School of Medicine, Hangzhou, China. zhang_yan@zju.edu.cn.
  • 16 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China. sunjinpeng@bjmu.edu.cn.
  • 17 Key Laboratory Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Shandong, China. sunjinpeng@bjmu.edu.cn.
  • # Contributed equally.
PMID: 33408414 DOI: 10.1038/s41586-020-03083-w
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.

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