9v6t | pdb_00009v6t
Cryo-EM structure of the GLPG1205-bound GPR84 receptor
Structural highlights
FunctionC562_ECOLX Electron-transport protein of unknown function. Publication Abstract from PubMedG-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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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