The orphan nuclear receptor Nurr1 is critical for the development, maintenance and protection of midbrain dopaminergic (mDA) neurons. Here we show that prostaglandin E1 (PGE1) and its dehydrated metabolite, PGA1, directly interact with the ligand-binding domain (LBD) of Nurr1 and stimulate its transcriptional function. We also report the crystallographic structure of Nurr1-LBD bound to PGA1 at 2.05 Å resolution. PGA1 couples covalently to Nurr1-LBD by forming a Michael adduct with Cys566, and induces notable conformational changes, including a 21° shift of the activation function-2 helix (H12) away from the protein core. Furthermore, PGE1/PGA1 exhibit neuroprotective effects in a Nurr1-dependent manner, prominently enhance expression of Nurr1 target genes in mDA neurons and improve motor deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mouse models of Parkinson’s disease. Based on these results, we propose that PGE1/PGA1 represent native ligands of Nurr1 and can exert neuroprotective effects on mDA neurons, via activation of Nurr1’s transcriptional function.

孤儿核受体 Nurr1 对中脑多巴胺能 (mDA) 神经元的发育、维持和保护至关重要。在这里，我们显示前列腺素 E1 (PGE1) 及其脱水代谢物 PGA1 直接与 Nurr1 的配体结合域 (LBD) 相互作用并刺激其转录功能。我们还报告了以 2.05 Å 分辨率与 PGA1 结合的 Nurr1-LBD 的晶体结构。PGA1 通过与 Cys566 形成迈克尔加合物与 Nurr1-LBD 共价偶联，并诱导显着的构象变化，包括激活功能 2 螺旋 (H12) 远离蛋白质核心的 21° 偏移。此外，PGE1/PGA1 以 Nurr1 依赖性方式表现出神经保护作用，显着增强 mDA 神经元中 Nurr1 靶基因的表达并改善 1-methyl-4-phenyl-1,2,3 的运动缺陷，6-四氢吡啶损伤的帕金森病小鼠模型。基于这些结果，我们提出 PGE1/PGA1 代表 Nurr1 的天然配体，可以通过激活 Nurr1 的转录功能对 mDA 神经元发挥神经保护作用。