Molecular basis of ligand-dependent Nurr1-RXRα activation
Small molecule compounds that activate transcription of Nurr1-retinoid X receptor alpha (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...
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eLife Sciences Publications Ltd
2023-04-01
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| Online Access: | https://elifesciences.org/articles/85039 |
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| author | Xiaoyu Yu Jinsai Shang Douglas J Kojetin |
| author_facet | Xiaoyu Yu Jinsai Shang Douglas J Kojetin |
| author_sort | Xiaoyu Yu |
| collection | DOAJ |
| description | Small molecule compounds that activate transcription of Nurr1-retinoid X receptor alpha (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, PPI, and 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 (RXRα homodimer agonists and Nurr1-RXRα heterodimer selective agonists that function as RXRα homodimer 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. |
| format | Article |
| id | doaj-art-63d92d0c1fcc4fdfb65d10b132435773 |
| institution | OA Journals |
| issn | 2050-084X |
| language | English |
| publishDate | 2023-04-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj-art-63d92d0c1fcc4fdfb65d10b1324357732025-08-20T02:12:25ZengeLife Sciences Publications LtdeLife2050-084X2023-04-011210.7554/eLife.85039Molecular basis of ligand-dependent Nurr1-RXRα activationXiaoyu Yu0https://orcid.org/0000-0003-0549-9560Jinsai Shang1Douglas J Kojetin2https://orcid.org/0000-0001-8058-6168Skaggs Graduate School of Chemical and Biological Sciences at Scripps Research, Jupiter, United States; Department of Integrative Structural and Computational Biology, Scripps Research and UF Scripps Biomedical Research, Jupiter, United StatesDepartment of Integrative Structural and Computational Biology, Scripps Research and UF Scripps Biomedical Research, Jupiter, United StatesDepartment of Integrative Structural and Computational Biology, Scripps Research and UF Scripps Biomedical Research, Jupiter, United States; Department of Molecular Medicine, Scripps Research and UF Scripps Biomedical Research, Jupiter, United StatesSmall molecule compounds that activate transcription of Nurr1-retinoid X receptor alpha (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, PPI, and 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 (RXRα homodimer agonists and Nurr1-RXRα heterodimer selective agonists that function as RXRα homodimer 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.https://elifesciences.org/articles/85039nuclear receptorsNMR spectroscopyligand bindingtranscription factorsbiophysicsprotein-protein interaction |
| spellingShingle | Xiaoyu Yu Jinsai Shang Douglas J Kojetin Molecular basis of ligand-dependent Nurr1-RXRα activation eLife nuclear receptors NMR spectroscopy ligand binding transcription factors biophysics protein-protein interaction |
| title | Molecular basis of ligand-dependent Nurr1-RXRα activation |
| title_full | Molecular basis of ligand-dependent Nurr1-RXRα activation |
| title_fullStr | Molecular basis of ligand-dependent Nurr1-RXRα activation |
| title_full_unstemmed | Molecular basis of ligand-dependent Nurr1-RXRα activation |
| title_short | Molecular basis of ligand-dependent Nurr1-RXRα activation |
| title_sort | molecular basis of ligand dependent nurr1 rxrα activation |
| topic | nuclear receptors NMR spectroscopy ligand binding transcription factors biophysics protein-protein interaction |
| url | https://elifesciences.org/articles/85039 |
| work_keys_str_mv | AT xiaoyuyu molecularbasisofliganddependentnurr1rxraactivation AT jinsaishang molecularbasisofliganddependentnurr1rxraactivation AT douglasjkojetin molecularbasisofliganddependentnurr1rxraactivation |