Structure of GPR101-Gs enables identification of ligands with rejuvenating potential
© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc..
GPR101 is an orphan G protein-coupled receptor actively participating in energy homeostasis. Here we report the cryo-electron microscopy structure of GPR101 constitutively coupled to Gs heterotrimer, which reveals unique features of GPR101, including the interaction of extracellular loop 2 within the 7TM bundle, a hydrophobic chain packing-mediated activation mechanism and the structural basis of disease-related mutants. Importantly, a side pocket is identified in GPR101 that facilitates in silico screening to identify four small-molecule agonists, including AA-14. The structure of AA-14-GPR101-Gs provides direct evidence of the AA-14 binding at the side pocket. Functionally, AA-14 partially restores the functions of GH/IGF-1 axis and exhibits several rejuvenating effects in wild-type mice, which are abrogated in Gpr101-deficient mice. In summary, we provide a structural basis for the constitutive activity of GPR101. The structure-facilitated identification of GPR101 agonists and functional analysis suggest that targeting this orphan receptor has rejuvenating potential.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:20 |
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| Enthalten in: |
Nature chemical biology - 20(2024), 4 vom: 12. Apr., Seite 484-492 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Yang, Zhao [VerfasserIn] |
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| Anmerkungen: |
Date Completed 29.03.2024 Date Revised 03.04.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s41589-023-01456-6 |
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| Förderinstitution / Projekttitel: |
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NLM364375671 |
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| 520 | |a GPR101 is an orphan G protein-coupled receptor actively participating in energy homeostasis. Here we report the cryo-electron microscopy structure of GPR101 constitutively coupled to Gs heterotrimer, which reveals unique features of GPR101, including the interaction of extracellular loop 2 within the 7TM bundle, a hydrophobic chain packing-mediated activation mechanism and the structural basis of disease-related mutants. Importantly, a side pocket is identified in GPR101 that facilitates in silico screening to identify four small-molecule agonists, including AA-14. The structure of AA-14-GPR101-Gs provides direct evidence of the AA-14 binding at the side pocket. Functionally, AA-14 partially restores the functions of GH/IGF-1 axis and exhibits several rejuvenating effects in wild-type mice, which are abrogated in Gpr101-deficient mice. In summary, we provide a structural basis for the constitutive activity of GPR101. The structure-facilitated identification of GPR101 agonists and functional analysis suggest that targeting this orphan receptor has rejuvenating potential | ||
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| 700 | 1 | |a Wang, Jun-Yan |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Fan |e verfasserin |4 aut | |
| 700 | 1 | |a Zhu, Kong-Kai |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Guo-Peng |e verfasserin |4 aut | |
| 700 | 1 | |a Guan, Ying |e verfasserin |4 aut | |
| 700 | 1 | |a Ning, Shang-Lei |e verfasserin |4 aut | |
| 700 | 1 | |a Lu, Yan |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Yu |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Chao |e verfasserin |4 aut | |
| 700 | 1 | |a Zheng, Yuan |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Shu-Hua |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Xin-Wen |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Ming-Wei |e verfasserin |4 aut | |
| 700 | 1 | |a Xiao, Peng |e verfasserin |4 aut | |
| 700 | 1 | |a Yi, Fan |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Cheng |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Peng-Ju |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Fei |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Bao-Hua |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Hua |e verfasserin |4 aut | |
| 700 | 1 | |a Yu, Xiao |e verfasserin |4 aut | |
| 700 | 1 | |a Gao, Ning |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Jin-Peng |e verfasserin |4 aut | |
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