Key metabolites act through specific G protein-coupled receptors (GPCRs) as extracellular signals of fuel availability and metabolic stress. Here, we focus on the succinate receptor SUCNR1/GPR91 and the long chain fatty acid receptor FFAR1/GPR40, for which 3D structural information is available. Like other small polar acidic metabolites, succinate is excreted from the cell by transporter proteins to bind to an extracellular, solvent-exposed pocket in SUCNR1. Non-metabolite pharmacological tool compounds are currently being designed based on the structure of the SUCNR1 binding pocket. In FFAR1, differently signaling lipid mimetics bind in two distinct membrane-exposed sites corresponding to each of the lipid bilayer leaflets. Conceivably endogenous lipid ligands gain access to these sites by way of the membrane and probably occupy both sites under physiological circumstances. Design of polar agonists for a dynamic, solvent-exposed pocket in FFAR1 underlines the possibility of structure-based approaches for development of novel tool compounds even in lipid sensing metabolite GPCRs.

中文翻译：

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小极性与大脂质代谢物的GPCR信号转导的结构基础-非代谢物配体的发现。

关键代谢产物通过特定的G蛋白偶联受体（GPCR）充当燃料供应和代谢压力的细胞外信号。在这里，我们专注于琥珀酸酯受体SUCNR1 / GPR91和长链脂肪酸受体FFAR1 / GPR40，它们具有3D结构信息。像其他小的极性酸性代谢物一样，琥珀酸酯通过转运蛋白从细胞中排出，与SUCNR1的细胞外，溶剂暴露的囊袋结合。当前正在基于SUCNR1结合口袋的结构设计非代谢药理学工具化合物。在FFAR1中，不同信号的脂质模拟物结合在两个与每个脂质双层小叶相对应的不同的膜暴露位点。可以想象，内源性脂质配体通过膜进入这些位点，并且在生理情况下可能占据两个位点。FFAR1中动态暴露于溶剂的口袋中的极性激动剂的设计强调了基于结构的方法开发新的工具化合物的可能性，即使在脂质传感代谢物GPCR中也是如此。