Molecular basis of ligand-dependent Nurr1-RXRα activation
Small molecule compounds that activate transcription of Nurr1-RXRα (NR4A2-NR2B1) nuclear receptor heterodimers are implicated in the treatment of neurodegenerative disorders, but function through poorly understood mechanisms. Here, we show that RXRα ligands activate Nurr1-RXRα through a mechanism that involves ligand-binding domain (LBD) heterodimer protein-protein 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-RXRα transcriptional activation by RXRα ligands is not correlated with classical RXRα agonism but instead correlated with weakening Nurr1-RXRα LBD heterodimer affinity and heterodimer dissociation. Our data inform a model by which pharmacologically distinct RXRα ligands (agonists and Nurr1-RXRα selective agonists that function as RXRα antagonists) operate as allosteric PPI inhibitors that release a transcriptionally active Nurr1 monomer from a repressive Nurr1-RXRα heterodimeric complex. These findings provide a molecular blueprint for ligand activation of Nurr1 transcription via small molecule targeting of Nurr1-RXRα.
Raw ITC thermograms and fitted data are provided as Figure 5-source data 1. Input files for NMR LineShapeKin simulated NMR data analysis in MATLAB are provided as Figure 6-source code 1 (zip file including two input files and one readme file). Raw data used for graphical plots are provided as Figure 1-source data 1 (Nurr1 + RXRα truncated construct luciferase reporter data), Figure 3-source data 1 (RXRα ligand treated Nurr1-RXRα/3xNBRE3-luciferase reporter data), Figure 4-source data 1 (RXRα ligand treated RXRα LBD TR-FRET), Figure 4-source data 2 (RXRα ligand treated RXRα/3xDR1-luciferase reporter data), and Figure 6-source data 1 (RXRα ligand treated Nurr1-RXRα LBD NMR-observed monomer species). All other data generated or analyzed during this study are included in the manuscript and supporting files.
Article and author information
National Institute on Aging (R01AG070719)
- Douglas J Kojetin
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
- Volker Dötsch, Goethe University, Germany
- Preprint posted: November 8, 2022 (view preprint)
- Received: November 18, 2022
- Accepted: April 26, 2023
- Accepted Manuscript published: April 27, 2023 (version 1)
© 2023, Yu et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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