Cryo‐EM structure of G‐protein‐coupled receptor GPR17 in complex with inhibitory G protein
Abstract GPR17 is a class A orphan G protein‐coupled receptor (GPCR) expressed in neurons and oligodendrocyte progenitors of the central nervous system (CNS). The signalling of GPR17 occurs through the heterotrimeric Gi, but its activation mechanism is unclear. Here, we employed cryo‐electron micros...
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| Format: | Article |
| Language: | English |
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Wiley
2022-12-01
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| Series: | MedComm |
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| Online Access: | https://doi.org/10.1002/mco2.159 |
| _version_ | 1826533388402556928 |
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| author | Fang Ye Thian‐Sze Wong Geng Chen Zhiyi Zhang Binghao Zhang Shiyi Gan Wei Gao Jiancheng Li Zhangsong Wu Xin Pan Yang Du |
| author_facet | Fang Ye Thian‐Sze Wong Geng Chen Zhiyi Zhang Binghao Zhang Shiyi Gan Wei Gao Jiancheng Li Zhangsong Wu Xin Pan Yang Du |
| author_sort | Fang Ye |
| collection | DOAJ |
| description | Abstract GPR17 is a class A orphan G protein‐coupled receptor (GPCR) expressed in neurons and oligodendrocyte progenitors of the central nervous system (CNS). The signalling of GPR17 occurs through the heterotrimeric Gi, but its activation mechanism is unclear. Here, we employed cryo‐electron microscopy (cryo‐EM) technology to elucidate the structure of activated GPR17‐Gi complex. The 3.02 Å resolution structure, together with mutagenesis studies, revealed that the extracellular loop2 of GPR17 occupied the orthosteric binding pocket to promote its self‐activation. The active GPR17 carried several typical microswitches like other class A GPCRs. Moreover, the Gi interacted with the key residues of transmembrane helix 3 (TM3), the amphipathic helix 8 (Helix8), and intracellular loops 3 (ICL3) in GPR17 to engage in the receptor core. In summary, our results highlight the activation mechanism of GPR17 from the structural basis. Elucidating the structural and activation mechanism of GPR17 may facilitate the pharmacological intervention for acute/chronic CNS injury. |
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| id | doaj.art-b0fec6be258f4f1b86b8d2688583ba8d |
| institution | Directory Open Access Journal |
| issn | 2688-2663 |
| language | English |
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| spelling | doaj.art-b0fec6be258f4f1b86b8d2688583ba8d2025-03-12T05:49:10ZengWileyMedComm2688-26632022-12-0134n/an/a10.1002/mco2.159Cryo‐EM structure of G‐protein‐coupled receptor GPR17 in complex with inhibitory G proteinFang Ye0Thian‐Sze Wong1Geng Chen2Zhiyi Zhang3Binghao Zhang4Shiyi Gan5Wei Gao6Jiancheng Li7Zhangsong Wu8Xin Pan9Yang Du10Kobilka Institute of Innovative Drug Discovery Shenzhen Key Laboratory of Steroid Drug Discovery and Development School of Medicine The Chinese University of Hong Kong Shenzhen Guangdong ChinaKobilka Institute of Innovative Drug Discovery Shenzhen Key Laboratory of Steroid Drug Discovery and Development School of Medicine The Chinese University of Hong Kong Shenzhen Guangdong ChinaKobilka Institute of Innovative Drug Discovery Shenzhen Key Laboratory of Steroid Drug Discovery and Development School of Medicine The Chinese University of Hong Kong Shenzhen Guangdong ChinaKobilka Institute of Innovative Drug Discovery Shenzhen Key Laboratory of Steroid Drug Discovery and Development School of Medicine The Chinese University of Hong Kong Shenzhen Guangdong ChinaKobilka Institute of Innovative Drug Discovery Shenzhen Key Laboratory of Steroid Drug Discovery and Development School of Medicine The Chinese University of Hong Kong Shenzhen Guangdong ChinaKobilka Institute of Innovative Drug Discovery Shenzhen Key Laboratory of Steroid Drug Discovery and Development School of Medicine The Chinese University of Hong Kong Shenzhen Guangdong ChinaKobilka Institute of Innovative Drug Discovery Shenzhen Key Laboratory of Steroid Drug Discovery and Development School of Medicine The Chinese University of Hong Kong Shenzhen Guangdong ChinaInstrumental Analysis Center Shenzhen University Shenzhen Guangdong ChinaKobilka Institute of Innovative Drug Discovery Shenzhen Key Laboratory of Steroid Drug Discovery and Development School of Medicine The Chinese University of Hong Kong Shenzhen Guangdong ChinaKobilka Institute of Innovative Drug Discovery Shenzhen Key Laboratory of Steroid Drug Discovery and Development School of Medicine The Chinese University of Hong Kong Shenzhen Guangdong ChinaKobilka Institute of Innovative Drug Discovery Shenzhen Key Laboratory of Steroid Drug Discovery and Development School of Medicine The Chinese University of Hong Kong Shenzhen Guangdong ChinaAbstract GPR17 is a class A orphan G protein‐coupled receptor (GPCR) expressed in neurons and oligodendrocyte progenitors of the central nervous system (CNS). The signalling of GPR17 occurs through the heterotrimeric Gi, but its activation mechanism is unclear. Here, we employed cryo‐electron microscopy (cryo‐EM) technology to elucidate the structure of activated GPR17‐Gi complex. The 3.02 Å resolution structure, together with mutagenesis studies, revealed that the extracellular loop2 of GPR17 occupied the orthosteric binding pocket to promote its self‐activation. The active GPR17 carried several typical microswitches like other class A GPCRs. Moreover, the Gi interacted with the key residues of transmembrane helix 3 (TM3), the amphipathic helix 8 (Helix8), and intracellular loops 3 (ICL3) in GPR17 to engage in the receptor core. In summary, our results highlight the activation mechanism of GPR17 from the structural basis. Elucidating the structural and activation mechanism of GPR17 may facilitate the pharmacological intervention for acute/chronic CNS injury.https://doi.org/10.1002/mco2.159cryo‐EMECL2GPCRGPR17protein structure |
| spellingShingle | Fang Ye Thian‐Sze Wong Geng Chen Zhiyi Zhang Binghao Zhang Shiyi Gan Wei Gao Jiancheng Li Zhangsong Wu Xin Pan Yang Du Cryo‐EM structure of G‐protein‐coupled receptor GPR17 in complex with inhibitory G protein MedComm cryo‐EM ECL2 GPCR GPR17 protein structure |
| title | Cryo‐EM structure of G‐protein‐coupled receptor GPR17 in complex with inhibitory G protein |
| title_full | Cryo‐EM structure of G‐protein‐coupled receptor GPR17 in complex with inhibitory G protein |
| title_fullStr | Cryo‐EM structure of G‐protein‐coupled receptor GPR17 in complex with inhibitory G protein |
| title_full_unstemmed | Cryo‐EM structure of G‐protein‐coupled receptor GPR17 in complex with inhibitory G protein |
| title_short | Cryo‐EM structure of G‐protein‐coupled receptor GPR17 in complex with inhibitory G protein |
| title_sort | cryo em structure of g protein coupled receptor gpr17 in complex with inhibitory g protein |
| topic | cryo‐EM ECL2 GPCR GPR17 protein structure |
| url | https://doi.org/10.1002/mco2.159 |
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