Molecular basis of activation of the orphan nuclear receptor Nurr1

激活孤儿核受体Nurr1(NR4A2)的小分子配体有望成为神经保护性治疗药物或佐剂，用于治疗衰老相关的神经退行性疾病和痴呆症，其特征是神经元功能丧失，包括帕金森氏病(PD)和阿尔茨海默病(AD)。Nurr1激活配体在阿尔茨海默病和帕金森病动物模型中显示出功能有效性。然而，尽管核受体被认为是配体依赖的转录因子，Nurr1的功能被认为不依赖于细胞中产生和存在的内源性配体的结合。已经报道了几种能激活Nurr1转录的合成配体，但大多数还没有被证实可以直接与Nurr1结合，其作用机制仍不清楚，这阻碍了针对AD和PD优化Nurr1配体的努力。此外，Nurr1作为单体和作为Nurr1-RXR异源二聚体调节转录。人工合成的RXR配体可以激活Nurr1-RXR异二聚体的转录，在AD和PD动物模型中也显示出功能功效。然而，RXR和RXR结合配体如何在结构水平上影响Nurr1-RXR的功能仍然知之甚少。在这个项目中，我们将通过机理研究来研究小分子配体如何在分子、结构和细胞水平上影响Nurr1和Nurr1-RXR的激活，在这个项目中，我们将使用核磁共振光谱、X射线结晶学、氢/氢交换、化学交联(XL-MS)和小角X射线散射以及生化和细胞功能分析来解决这些知识差距。这些数据将为设计新的和改进的Nurr1激活配体提供信息，以确定直接靶向Nurr1或通过RXR间接靶向治疗AD和PD是可行的选择

Small molecule ligands that activate the orphan nuclear receptor Nurr1 (NR4A2) hold promise as neuroprotective therapeutic agents or adjuvants to aging-associated neurodegenerative and dementia disorders characterized by a loss of neuron function including Parkinson's disease (PD) and Alzheimer's disease (AD). Nurr1 activating ligands show functional efficacy in animal models of AD and PD. However, although nuclear receptors are considered to be ligand-dependent transcription factors, Nurr1 is thought to function independent of binding an endogenous ligand that is produced and present in cells. Several synthetic ligands that activate Nurr1 transcription have been reported, but most have not been validated to directly bind Nurr1 and their mechanism of action remains unknown, which has stunted efforts to optimize Nurr1 ligands for AD and PD. Furthermore, Nurr1 regulates transcription as a monomer and as a Nurr1-RXR heterodimer. Synthetic RXR ligands that activate transcription of Nurr1-RXR heterodimers also display functional efficacy in animal models of AD and PD. However, it remains poorly understood how RXR and RXR-binding ligands impact the function of Nurr1-RXR on the structural level. In this project, we will address these knowledge gaps using mechanistic studies to define how small molecule ligands impact Nurr1 and Nurr1-RXR activation on the molecular, structural, and cellular levels using NMR spectroscopy, X-ray crystallography, mass spectrometry coupled to hydrogen/deuterium exchange (HDX-MS) and chemical crosslinking (XL-MS) and small angle X-ray scattering along with biochemical and cellular functional assays. These data will inform the design of new and improved Nurr1 activating ligands to determine if direct targeting of Nurr1 or indirect targeting via RXR is a viable option for AD and PD treatment