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Pro-phagocytic function and structural basis of GPR84 signaling
Open accessPreprint — published as 10.1038/s41467-023-41201-0 · Paper page
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 the phagocytic activities of macrophages. In this study, we first showed that the activation of GPR84 by the synthetic agonist 6-OAU could synergize with the blockade of CD47 on cancer cells to induce phagocytosis of cancer cells by macrophages. Then, we determined a high-resolution structure of the GPR84-Gi signaling complex with 6-OAU. This structure revealed a completely 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, our structure also suggested the mechanism for the high selectivity of GPR84 for MCFAs and the potential routes of ligand binding and dissociation. Our results provide a framework for understanding GPR84 signaling and developing new drugs targeting GPR84.
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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
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Metadata
- 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
- 2023-02-15
- Volume
- 14
- Issue
- 1
- Pages
- 5706-5706
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC10502086
- OpenAlex
- W4386732685
- Cited by
- 46
- References
- 1
- 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 and Human Services (R35GM128641)
- UK Research and Innovation
- Research Councils UK (BB/T000562/1)
- National Natural Science Foundation of China (T2221005)
- University of Science and Technology of China
- National Supercomputing Centre Singapore
- National Institutes of Health
- Biotechnology and Biological Sciences Research Council (BB/T000562/1)
- Biomedical Research Council
- National Institute of General Medical Sciences (R35GM128641)
- 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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