分类: 药物科学 >> 结构生物学 提交时间: 2024-02-29
摘要: Succinic acid, a tricarboxylic acid (TCA) cycle intermediate, significantly influences mitochondrial reactive oxygen species homeostasis through the G protein-coupled succinate receptor (SUCR1, also called GPR91), linking it to various physiological and pathological processes. Despite SUCR1’s pivotal role in mediating effects leading to liver fibrosis, hypertension, angiogenesis, inflammation, and offering a therapeutic target for multiple diseases, its activation mechanism by diverse ligands and interaction with downwards G protein remains poorly understood. This study presents the cryo-electron microscopy (cryo-EM) structures of SUCR1 in complex with inhibitory G protein (Gi) bound to succinic acid, maleic acid, and compound 31, a high-affinity agonist. These structures elucidate the distinct ligand binding modes, uncover the activation signal cascade, and detail the G protein coupling mechanism of SUCR1. Our findings provide a comprehensive structural basis for SUCR1 activation, paving the way for structure-based drug design aimed at SUCR1-related pathologies.
分类: 药物科学 >> 结构生物学 提交时间: 2024-02-24
摘要: The orphan receptor GPR30, previously classified as a G protein-coupled estrogen receptor (GPER), has been a subject of debate regarding its ligand specificity. Through an integrative approach combining structure elucidation, biochemical binding, and cell signaling assays, we demonstrate that estrogen does not directly bind to or activate GPR30. Cryo-EM structures of GPR30 reveal an unexpected hydrophilic ligand-binding pocket, with striking differences from classical hydrophobic steroid-binding sites, inconsistent with estrogen binding. We further confirmed hydrophilic agonists like Lys05 as true activators of GPR30, providing structural insights into their binding mechanism and receptor activation. Our findings necessitate a paradigm shift in defining GPR30’s role in estrogen signaling, indicating that its activation occurs through mechanisms independent of estrogen binding. This study opens new avenues for developing targeted GPR30 ligands and reinterpreting its role in estrogen-mediated processes.