8g05
Cryo-EM structure of an orphan GPCR-Gi protein signaling complexCryo-EM structure of an orphan GPCR-Gi protein signaling complex
Structural highlights
FunctionGPR84_HUMAN G protein-coupled receptor that responds endogenously to dietary fatty acids or nutrient, specifically medium-chain free fatty acid (FFA) with carbon chain lengths of C9 to C14. Capric acid (C10:0), undecanoic acid (C11:0) and lauric acid (C12:0) are the most potent agonists (PubMed:16966319). In immune cells, functions as a pro-inflammatory receptor via 6-OAU and promotes the expression of pro-inflammatory mediators such as TNFalpha, IL-6 and IL-12B as well as stimulating chemotactic responses through activation of signaling mediators AKT, ERK and NF-kappa-B (By similarity). In addition, triggers increased bacterial adhesion and phagocytosis in macrophages and regulates pro-inflammatory function via enhancing NLRP3 inflammasome activation (By similarity). Plays also an important role in inflammation by modulating neutrophil functions (By similarity). Mechanistically, promotes neutrophil chemotaxis, reactive oxygen species (ROS) production and degranulation via LYN-AKT/ERK pathway (By similarity). To regulate ROS, communicates with the two formyl peptide receptors FPR2 and FPR1 to control the NADPH oxidase activity in neutrophils (PubMed:33789297).[UniProtKB:Q8CIM5][1] [2] Publication Abstract from PubMedGPR84 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. Pro-phagocytic function and structural basis of GPR84 signaling.,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 Nat Commun. 2023 Sep 14;14(1):5706. doi: 10.1038/s41467-023-41201-0. PMID:37709767[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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