Pro-phagocytic function and structural basis of GPR84 signaling

Pro-phagocytic function and structural basis of GPR84 signaling

Nature Communications

10.1038/s41467-023-41201-0

https://doi.org/10.1038/s41467-023-41201-0

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

14 September 2023

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. (2023). Pro-phagocytic function and structural basis of GPR84 signaling. Nature Communications, 14(1). https://doi.org/10.1038/s41467-023-41201-0

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.

Attribution 4.0 International (CC BY 4.0)

This research is supported by core funding from: A*STAR - Bioinformatics Institute.

https://oar.a-star.edu.sg/communities-collections/articles/22715

2041-1723

Bioinformatics Institute