Pro-phagocytic function and structural basis of GPR84 signaling
Abstract 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 phag...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-09-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-41201-0 |
| _version_ | 1797558275918528512 |
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| author | Xuan Zhang Yujing Wang Shreyas Supekar Xu Cao Jingkai Zhou Jessica Dang Siqi Chen Laura Jenkins Sara Marsango Xiu Li Guibing Liu Graeme Milligan Mingye Feng Hao Fan Weimin Gong Cheng Zhang |
| author_facet | Xuan Zhang Yujing Wang Shreyas Supekar Xu Cao Jingkai Zhou Jessica Dang Siqi Chen Laura Jenkins Sara Marsango Xiu Li Guibing Liu Graeme Milligan Mingye Feng Hao Fan Weimin Gong Cheng Zhang |
| author_sort | Xuan Zhang |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-03-10T17:27:57Z |
| format | Article |
| id | doaj.art-f928a8c42c4f4cda90c65d67e6687d23 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-10T17:27:57Z |
| publishDate | 2023-09-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-f928a8c42c4f4cda90c65d67e6687d232023-11-20T10:07:22ZengNature PortfolioNature Communications2041-17232023-09-0114111210.1038/s41467-023-41201-0Pro-phagocytic function and structural basis of GPR84 signalingXuan Zhang0Yujing Wang1Shreyas Supekar2Xu Cao3Jingkai Zhou4Jessica Dang5Siqi Chen6Laura Jenkins7Sara Marsango8Xiu Li9Guibing Liu10Graeme Milligan11Mingye Feng12Hao Fan13Weimin Gong14Cheng Zhang15Division of Life Sciences and Medicine, University of Science and Technology of ChinaDivision of Life Sciences and Medicine, University of Science and Technology of ChinaBioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR)Department of Immuno-Oncology, Beckman Research Institute, City of Hope Comprehensive Cancer CenterDepartment of Immuno-Oncology, Beckman Research Institute, City of Hope Comprehensive Cancer CenterDepartment of Immuno-Oncology, Beckman Research Institute, City of Hope Comprehensive Cancer CenterDepartment of Immuno-Oncology, Beckman Research Institute, City of Hope Comprehensive Cancer CenterCentre for Translational Pharmacology, School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, University of GlasgowCentre for Translational Pharmacology, School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, University of GlasgowDivision of Life Sciences and Medicine, University of Science and Technology of ChinaDivision of Life Sciences and Medicine, University of Science and Technology of ChinaCentre for Translational Pharmacology, School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, University of GlasgowDepartment of Immuno-Oncology, Beckman Research Institute, City of Hope Comprehensive Cancer CenterBioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR)Division of Life Sciences and Medicine, University of Science and Technology of ChinaDepartment of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, University of PittsburghAbstract 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.https://doi.org/10.1038/s41467-023-41201-0 |
| spellingShingle | Xuan Zhang Yujing Wang Shreyas Supekar Xu Cao Jingkai Zhou Jessica Dang Siqi Chen Laura Jenkins Sara Marsango Xiu Li Guibing Liu Graeme Milligan Mingye Feng Hao Fan Weimin Gong Cheng Zhang Pro-phagocytic function and structural basis of GPR84 signaling Nature Communications |
| title | Pro-phagocytic function and structural basis of GPR84 signaling |
| title_full | Pro-phagocytic function and structural basis of GPR84 signaling |
| title_fullStr | Pro-phagocytic function and structural basis of GPR84 signaling |
| title_full_unstemmed | Pro-phagocytic function and structural basis of GPR84 signaling |
| title_short | Pro-phagocytic function and structural basis of GPR84 signaling |
| title_sort | pro phagocytic function and structural basis of gpr84 signaling |
| url | https://doi.org/10.1038/s41467-023-41201-0 |
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