Pro-phagocytic function and structural basis of GPR84 signaling
© 2023. Springer Nature Limited..
GPR84 is a unique orphan G protein-coupled receptor (GPCR) that can be activated by endogenous medium-chain fatty acids (MCFAs). The signaling of GPR84 is largely pro-inflammatory, which can augment inflammatory response, and GPR84 also functions as a pro-phagocytic receptor to enhance phagocytic activities of macrophages. In this study, we show that the activation of GPR84 by the synthetic agonist 6-OAU can synergize with the blockade of CD47 on cancer cells to induce phagocytosis of cancer cells by macrophages. We also determine a high-resolution structure of the GPR84-Gi signaling complex with 6-OAU. This structure reveals an occluded binding pocket for 6-OAU, the molecular basis of receptor activation involving non-conserved structural motifs of GPR84, and an unusual Gi-coupling interface. Together with computational docking and simulations studies, this structure also suggests a mechanism for the high selectivity of GPR84 for MCFAs and a potential routes of ligand binding and dissociation. These results provide a framework for understanding GPR84 signaling and developing new drugs targeting GPR84.
| Errataetall: | |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:14 |
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| Enthalten in: |
Nature communications - 14(2023), 1 vom: 14. Sept., Seite 5706 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Zhang, Xuan [VerfasserIn] |
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| Links: |
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| Themen: |
Fatty Acids |
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| Anmerkungen: |
Date Completed 18.09.2023 Date Revised 09.12.2023 published: Electronic UpdateOf: Res Sq. 2023 Feb 15;:. - PMID 36824923 Citation Status MEDLINE |
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| doi: |
10.1038/s41467-023-41201-0 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM362069948 |
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| 520 | |a GPR84 is a unique orphan G protein-coupled receptor (GPCR) that can be activated by endogenous medium-chain fatty acids (MCFAs). The signaling of GPR84 is largely pro-inflammatory, which can augment inflammatory response, and GPR84 also functions as a pro-phagocytic receptor to enhance phagocytic activities of macrophages. In this study, we show that the activation of GPR84 by the synthetic agonist 6-OAU can synergize with the blockade of CD47 on cancer cells to induce phagocytosis of cancer cells by macrophages. We also determine a high-resolution structure of the GPR84-Gi signaling complex with 6-OAU. This structure reveals an occluded binding pocket for 6-OAU, the molecular basis of receptor activation involving non-conserved structural motifs of GPR84, and an unusual Gi-coupling interface. Together with computational docking and simulations studies, this structure also suggests a mechanism for the high selectivity of GPR84 for MCFAs and a potential routes of ligand binding and dissociation. These results provide a framework for understanding GPR84 signaling and developing new drugs targeting GPR84 | ||
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| 700 | 1 | |a Wang, Yujing |e verfasserin |4 aut | |
| 700 | 1 | |a Supekar, Shreyas |e verfasserin |4 aut | |
| 700 | 1 | |a Cao, Xu |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Jingkai |e verfasserin |4 aut | |
| 700 | 1 | |a Dang, Jessica |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Siqi |e verfasserin |4 aut | |
| 700 | 1 | |a Jenkins, Laura |e verfasserin |4 aut | |
| 700 | 1 | |a Marsango, Sara |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Xiu |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Guibing |e verfasserin |4 aut | |
| 700 | 1 | |a Milligan, Graeme |e verfasserin |4 aut | |
| 700 | 1 | |a Feng, Mingye |e verfasserin |4 aut | |
| 700 | 1 | |a Fan, Hao |e verfasserin |4 aut | |
| 700 | 1 | |a Gong, Weimin |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Cheng |e verfasserin |4 aut | |
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