Pro-phagocytic function and structural basis of GPR84 signaling
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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-G i 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 i -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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Cites
Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764 · see citing works
Highly accurate protein structure prediction for the human proteome
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“Non-conserved structural motifs of GPR84 and receptor activation SincethereisnoexperimentallysolvedinactivestructureofGPR84,we used the Alphafold predicted structure of apo GPR84 54,55 in our structuralcomparison analysis.”
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Phagocytosis: An Immunobiologic Process
Gordon, S. (2016) · Immunity · doi:10.1016/j.immuni.2016.02.026 · Cited by 902 · see citing works
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- 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., & Zhang, C.
- Affiliations
- University of Science and Technology of China (CN)
- Agency for Science, Technology and Research (SG)
- City Of Hope National Medical Center (US)
- University of Glasgow (GB)
- University of Pittsburgh (US)
- Corresponding author
- Milligan, Graeme
- Feng, Mingye
- Fan, Hao
- Gong, Weimin
- Zhang, Cheng
- ORCID
- Venue
- Nature Communications
- Published
- 2023-09-14
- Volume
- 14
- Issue
- 1
- Pages
- 5706-5706
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC10502086
- OpenAlex
- W4386732685
- Cited by
- 46
- References
- 5
- Citations by year
- 2026: 16 · 2025: 17 · 2024: 9 · 2023: 4
- FWCI
- 4.09
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Research Square (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion, cc-by)
- PubMed Central (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (R35GM128641)
- RCUK | Biotechnology and Biological Sciences Research Council (BB/T000562/1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
- Keywords
- GPR84, orphan G protein-coupled receptor, medium-chain fatty acids, CD47 blockade, phagocytosis, macrophages, binding pocket, fatty acid selectivity, pro-inflammatory signaling
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