Molecular insights into ligand recognition and signaling of OXGR1.

ABSTRACT: GPR99/OXGR1 is a G protein-coupled receptor (GPCR) with two endogenous agonists, the tricarboxylic acid cycle derivative 2-oxoglutarate (α-ketoglutarate) and the inflammatory mediator cysteinyl leukotriene E4 (LTE₄), hence also termed CysLT3 receptor. How GPR99/OXGR1 recognizes two distinct ligands is a biologically important question. Here we present cryo-EM structures of GPR99/OXGR1-Gq complexed with oxoglutarate and LTE₄, respectively. The oxoglutarate-bound structure shows a binding pocket surrounded by the transmembrane domains (TM), with a primary site and an accessory site for simultaneous binding of two oxoglutarate molecules for full activation of the receptor. The TM binding pocket, however, is too small to accommodate the cysteinyl leukotriene LTE₄

SUBMITTER: Liu A 

PROVIDER: S-EPMC12714840 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature