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Pro-phagocytic function and structural basis of GPR84 signaling.
- Source :
-
Nature communications [Nat Commun] 2023 Sep 14; Vol. 14 (1), pp. 5706. Date of Electronic Publication: 2023 Sep 14. - Publication Year :
- 2023
-
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-G <subscript>i</subscript> 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 G <subscript>i</subscript> -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.<br /> (© 2023. Springer Nature Limited.)
- Subjects :
- Macrophages
Phagocytosis
Fatty Acids
Phagocytes
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 14
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 37709767
- Full Text :
- https://doi.org/10.1038/s41467-023-41201-0