The Takara Bio Endowed Division, Department of Biomolecular Recognition, Institute for Protein Research, Osaka University, Open Laboratories of Advanced Bioscience and Biotechnology, Furuedai, Suita, Osaka, Japan.
EMBO J. 2010 Oct 6;29(19):3395-407. doi: 10.1038/emboj.2010.197. Epub 2010 Aug 17.
The nuclear receptor, peroxisome proliferator-activated receptor γ (PPARγ), recognizes various synthetic and endogenous ligands by the ligand-binding domain. Fatty-acid metabolites reportedly activate PPARγ through conformational changes of the Ω loop. Here, we report that serotonin metabolites act as endogenous agonists for PPARγ to regulate macrophage function and adipogenesis by directly binding to helix H12. A cyclooxygenase inhibitor, indomethacin, is a mimetic agonist of these metabolites. Crystallographic analyses revealed that an indole acetate functions as a common moiety for the recognition by the sub-pocket near helix H12. Intriguingly, a serotonin metabolite and a fatty-acid metabolite each bind to distinct sub-pockets, and the PPARγ antagonist, T0070907, blocked the fatty-acid agonism, but not that of the serotonin metabolites. Mutational analyses on receptor-mediated transcription and coactivator binding revealed that each metabolite individually uses coregulator and/or heterodimer interfaces in a ligand-type-specific manner. Furthermore, the inhibition of the serotonin metabolism reduced the expression of the endogenous PPARγ-target gene. Collectively, these results suggest a novel agonism, in which PPARγ functions as a multiple sensor in response to distinct metabolites.
核受体过氧化物酶体增殖物激活受体 γ (PPARγ) 通过配体结合域识别各种合成和内源性配体。据报道，脂肪酸代谢物通过 Ω 环的构象变化激活 PPARγ。在这里，我们报告说，5-羟色胺代谢物通过直接结合螺旋 H12 作为内源性激动剂发挥作用，调节巨噬细胞功能和脂肪生成。环氧化酶抑制剂吲哚美辛是这些代谢物的模拟激动剂。晶体学分析表明，吲哚乙酸作为识别螺旋 H12 附近亚口袋的共同部分。有趣的是，5-羟色胺代谢物和脂肪酸代谢物各结合到不同的亚口袋，PPARγ 拮抗剂 T0070907 阻断了脂肪酸激动剂，但不阻断 5-羟色胺代谢物的激动剂。对受体介导的转录和共激活剂结合的突变分析表明，每种代谢物各自以配体类型特异性的方式使用共调节剂和/或异二聚体界面。此外，抑制 5-羟色胺代谢会降低内源性 PPARγ 靶基因的表达。总之，这些结果表明了一种新的激动作用，其中 PPARγ 作为一个多传感器，对不同的代谢物作出反应。
