Zhang, X. et al. (2023) Pro-phagocytic function and structural basis of GPR84 signaling. Nature Communications, 14, 5706. (doi: 10.1038/s41467-023-41201-0) (PMID:37709767) (PMCID:PMC10502086)
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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.
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Milligan, Professor Graeme and Jenkins, Mrs Laura and Marsango, Dr Sara |
| Authors: | Zhang, X., Wang, Y., Supekar, S., Cao, X., Zhou, J., Dang, J., Chen, S., Jenkins, L., Marsango, S., Li, X., Liu, G., Milligan, G., Feng, M., Fan, H., Gong, W., and Zhang, C. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Molecular Biosciences |
| Journal Name: | Nature Communications |
| Publisher: | Nature Research |
| ISSN: | 2041-1723 |
| ISSN (Online): | 2041-1723 |
| Copyright Holders: | Copyright © 2023 The Authors |
| First Published: | First published in Nature Communications 14: 5706 |
| Publisher Policy: | Reproduced under a Creative Commons License |
| Related URLs: | |
| Data DOI: | 10.2210/pdb8G05/pdb |
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