Pro-phagocytic function and structural basis of GPR84 signaling

• Published in: Nature communications Vol. 14; no. 1; pp. 5706 - 12
• Main Authors: Zhang, Xuan, Wang, Yujing, Supekar, Shreyas, Cao, Xu, Zhou, Jingkai, Dang, Jessica, Chen, Siqi, Jenkins, Laura, Marsango, Sara, Li, Xiu, Liu, Guibing, Milligan, Graeme, Feng, Mingye, Fan, Hao, Gong, Weimin, Zhang, Cheng
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 14.09.2023; Nature Publishing Group UK; Nature Portfolio
• Subjects: Agonists; Antibodies; Binding; Biology; Bone marrow; Cancer; Drug delivery; Fatty Acids; G protein-coupled receptors; Inflammation; Inflammatory response; Life sciences; Ligands; Macrophages; Phagocytes; Phagocytosis; Physiology; Proteins; Receptor mechanisms; Receptors; Signal Transduction; Synergism; Whooping cough
• ISSN: 2041-1723; 2041-1723
• DOI: 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 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 -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.