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Updated: Aug 27, 2026

Modeling Ligands into Maps Derived from Electron Cryomicroscopy
Published on: July 19, 2024
Structural insights into ligand recognition and activation of the human oxoglutarate receptor OXGR1
Tingshuai Ma1,2, Ziyan Chen3, Enyuan Liang4,5
1Institute of Bio-Architecture and Bio-Interactions (IBABI), Shenzhen Medical Academy of Research and Translation (SMART), Shenzhen, Guangdong, China.
Abstract:
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.
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