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). 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. Furthermore, Nurr1 regulates transcription as a monomer and as a Nurr1-RXR heterodimer. Synthetic RXR ligands can activate transcription of Nurr1- RXR heterodimers, but 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 de?ne 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.
Nurr1 is a transcription factor implicated as a therapeutic drug target in aging-associated neurodegenerative and dementia disorders characterized by a loss of neuron function including including Parkinson's and Alzheimer's diseases. Little is known mechanistically how Nurr1 is regulated by drug-like small molecules, a knowledge gap that we aim to resolve as a long-term goal of this project. Successful outcomes from our work will aid in the rational design of novel Nurr1 therapeutics.