School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore, 637551, Singapore.
Neurodegeneration Research Laboratory, National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore, 308433, Singapore.
Neuromolecular Med. 2022 Dec;24(4):469-478. doi: 10.1007/s12017-022-08712-3. Epub 2022 Apr 28.
The orphan nuclear receptor Nurr1 is critical for the development, maintenance, and protection of midbrain dopaminergic neurons. Recently, we demonstrated that prostaglandins E1 (PGE1) and PGA1 directly bind to the ligand-binding domain (LBD) of Nurr1 and stimulate its transcriptional activation function. In this direction, here we report the transcriptional activation of Nurr1 by PGA2, a dehydrated metabolite of PGE2, through physical binding ably supported by NMR titration and crystal structure. The co-crystal structure of Nurr1-LBD bound to PGA2 revealed the covalent coupling of PGA2 with Nurr1-LBD through Cys566. PGA2 binding also induces a 21° shift of the activation function 2 (AF-2) helix H12 away from the protein core, similar to that observed in the Nurr1-LBD-PGA1 complex. We also show that PGA2 can rescue the locomotor deficits and neuronal degeneration in LRRK2 G2019S transgenic fly models.
孤儿核受体 Nurr1 对于中脑多巴胺能神经元的发育、维持和保护至关重要。最近，我们证明前列腺素 E1（PGE1）和 PGA1 可直接与 Nurr1 的配体结合域（LBD）结合，并刺激其转录激活功能。在这一方向上，我们报告了 PGA2（PGE2 的脱水代谢物）通过 NMR 滴定和晶体结构有力支持的物理结合对 Nurr1 的转录激活。与 PGA2 结合的 Nurr1-LBD 的共晶结构揭示了 PGA2 通过半胱氨酸 566 与 Nurr1-LBD 的共价偶联。PGA2 结合还诱导激活功能 2（AF-2）螺旋 H12 相对于蛋白质核心发生 21°的位移，类似于在 Nurr1-LBD-PGA1 复合物中观察到的情况。我们还表明，PGA2 可以挽救 LRRK2 G2019S 转基因蝇模型中的运动缺陷和神经元退化。
