Molecular basis of ligand-dependent Nurr1-RXRα activation

Small molecule compounds that activate transcription of Nurr1-RXR (NR4A2-NR2B1) nuclear receptor heterodimers are implicated in the treatment of neurodegenerative disorders, but function through poorly understood mechanisms. Here, we show that RXR ligands activate Nurr1-RXR through a mechanism that involves ligand-binding domain (LBD) heterodimer proteinprotein interaction (PPI) inhibition, a paradigm distinct from classical pharmacological mechanisms of ligand-dependent nuclear receptor modulation. NMR spectroscopy, protein-protein interaction, cellular transcription assays show that Nurr1-RXR transcriptional activation by RXR ligands is not correlated with classical RXR agonism but instead correlated with weakening Nurr1-RXR LBD heterodimer affinity and heterodimer dissociation. Our data inform a model by which pharmacologically distinct RXR ligands (agonists and Nurr1-RXR selective agonists that function as RXR antagonists) operate as allosteric PPI inhibitors that release a transcriptionally active Nurr1 monomer from a repressive Nurr1-RXR heterodimeric complex. These findings provide a molecular blueprint for ligand activation of Nurr1 transcription via small molecule targeting of Nurr1-RXR.