Pro-phagocytic function and structural basis of GPR84 signaling

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 () and Cheng Zhang ()
Additional contact information
Xuan Zhang: University of Science and Technology of China
Yujing Wang: University of Science and Technology of China
Shreyas Supekar: Technology and Research (A*STAR)
Xu Cao: City of Hope Comprehensive Cancer Center
Jingkai Zhou: City of Hope Comprehensive Cancer Center
Jessica Dang: City of Hope Comprehensive Cancer Center
Siqi Chen: City of Hope Comprehensive Cancer Center
Laura Jenkins: University of Glasgow
Sara Marsango: University of Glasgow
Xiu Li: University of Science and Technology of China
Guibing Liu: University of Science and Technology of China
Graeme Milligan: University of Glasgow
Mingye Feng: City of Hope Comprehensive Cancer Center
Hao Fan: Technology and Research (A*STAR)
Weimin Gong: University of Science and Technology of China
Cheng Zhang: University of Pittsburgh School of Medicine, University of Pittsburgh

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-41201-0

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