Structural insights into ligand recognition and activation of the human oxoglutarate receptor OXGR1

The human oxoglutarate receptor 1 (OXGR1/GPR99) is a G protein–coupled receptor (GPCR) expressed in the kidney that senses metabolic signals. In addition, OXGR1 also responds to immunometabolites in the airway epithelium and contributes to innate airway defense. Despite the identification of endogenous ligands α-ketoglutarate (α-KG) and itaconate (ITN), the molecular basis of these metabolite recognition and activation remains poorly understood. Here, we present cryo-electron microscopy structures of human OXGR1 in complex with Gq protein bound to α-KG and ITN, helping to reveal key binding interactions and conformational changes associated with receptor activation. Structure-activity relationship analyses using diverse dicarboxylates elucidate the determinants of ligand specificity, including carbon chain length, functional groups, and spatial configuration. Furthermore, we show a pH-dependent regulatory mechanism, with maximal OXGR1 activity at physiological pH 7.4, indicating its regulation in the renal environment. Together, these findings elucidate the structural basis of metabolite sensing by OXGR1 and provide a framework for rational drug discovery targeting OXGR1-associated disorders. OXGR1 is involved in metabolic signals to kidney and airway physiology. Here the authors define how α-ketoglutarate and itaconate are recognized by OXGR1, reveal ligand-driven receptor activation, and uncover pH-dependent regulation of its signaling.