9upy

Cryo-EM structure of the ZQ16-bound GPR84 receptor-Gi complex

spinqualitylabelsall models 9upy, resolution 3.10Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9upy is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.1Å Ligands: A1L9K Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function GPR84_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] Publication Abstract from PubMed G-protein-coupled receptor 84 (GPR84) is an orphan class A GPCR selectively activated by medium chain fatty acids and highly expressed in immune cells, where it modulates pro-inflammatory signaling. The structural basis of GPR84 inactivation and antagonism has remained unclear, limiting the rational design of pathway-selective modulators despite its clinical relevance in metabolic inflammation and fibrotic diseases. Here, we report cryo-electron microscopy structures of human GPR84 in inactive and active states. The 3.5 A inactive structure bound to the antagonist GLPG1205 reveals a lid-like conformation of extracellular loop 2 and an inward reorientation of Arg172, with the antagonist head group blocking the allosteric sodium-binding site. Molecular dynamics simulations further support these findings, identifying an aberrant TM5, TM6 lateral entry gate. By contrast, the 3.17 A agonist ZQ-16, Galphai complex, shows a rearranged toggle switch and comparative analyses highlight extracellular loop 2 conformational plasticity. Immune functional assays in THP-1 cells demonstrated that ZQ-16 elicited GPR84-dependent activation and cytokine production, which were effectively abrogated by GLPG1205. Mutagenesis combined with functional assays validates key ligand interactions, providing a framework for the rational design of pathway selective GPR84 modulators. Pharmacological modulation of GPR84 revealed by dual states structures and immune functional assays.,Choi MK, Park DJ, Kim P, Choi HS, Myung S, Yoo Y, Chang N, Yoon GY, Kang HJ, Ha SJ, Cho HS Exp Mol Med. 2026 Sep 10. doi: 10.1038/s12276-026-01841-w. PMID:42722702 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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