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Here, we show that RXR\u03b1 ligands activate Nurr1-RXR\u03b1 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-RXR\u03b1 transcriptional activation by RXR\u03b1 ligands is not correlated with classical RXR\u03b1 agonism but instead correlated with weakening Nurr1-RXR\u03b1 LBD heterodimer affinity and heterodimer dissociation. Our data inform a model by which pharmacologically distinct RXR\u03b1 ligands (RXR\u03b1 homodimer agonists and Nurr1-RXR\u03b1 heterodimer selective agonists that function as RXR\u03b1 homodimer antagonists) operate as allosteric PPI inhibitors that release a transcriptionally active Nurr1 monomer from a repressive Nurr1-RXR\u03b1 heterodimeric complex. These findings provide a molecular blueprint for ligand activation of Nurr1 transcription via small molecule targeting of Nurr1-RXR\u03b1.<\/jats:p>","DOI":"10.7554\/elife.85039","type":"journal-article","created":{"date-parts":[[2023,4,27]],"date-time":"2023-04-27T08:00:41Z","timestamp":1682582441000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.85039","source":"Crossref","is-referenced-by-count":21,"title":["Molecular basis of ligand-dependent Nurr1-RXR\u03b1 activation"],"prefix":"10.7554","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0549-9560","authenticated-orcid":true,"given":"Xiaoyu","family":"Yu","sequence":"first","affiliation":[{"name":"Skaggs Graduate School of Chemical and Biological Sciences at Scripps Research","place":["Jupiter, United States"]},{"name":"Department of Integrative Structural and Computational Biology, Scripps Research and UF Scripps Biomedical Research","place":["Jupiter, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinsai","family":"Shang","sequence":"additional","affiliation":[{"name":"Department of Integrative Structural and Computational Biology, Scripps Research and UF Scripps Biomedical Research","place":["Jupiter, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8058-6168","authenticated-orcid":true,"given":"Douglas J","family":"Kojetin","sequence":"additional","affiliation":[{"name":"Department of Integrative Structural and Computational Biology, Scripps Research and UF Scripps Biomedical Research","place":["Jupiter, United States"]},{"name":"Department of Molecular Medicine, Scripps Research and UF Scripps Biomedical Research","place":["Jupiter, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4374","published-online":{"date-parts":[[2023,4,27]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","first-page":"35118","DOI":"10.1074\/jbc.M201707200","article-title":"Defining requirements for heterodimerization between the retinoid X receptor and the orphan nuclear receptor Nurr1","volume":"277","author":"Aarnisalo","year":"2002","journal-title":"The Journal of Biological Chemistry"},{"key":"bib2","doi-asserted-by":"publisher","DOI":"10.1101\/2022.08.18.504385","article-title":"androgen receptor condensates as drug targets","volume-title":"bioRxiv","author":"Basu","year":"2022"},{"key":"bib3","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1016\/bs.mie.2015.05.001","article-title":"Calculations and publication-quality illustrations for analytical ultracentrifugation data","volume":"562","author":"Brautigam","year":"2015","journal-title":"Methods in Enzymology"},{"key":"bib4","doi-asserted-by":"publisher","first-page":"882","DOI":"10.1038\/nprot.2016.044","article-title":"Integration and global analysis of isothermal titration calorimetry data for studying macromolecular interactions","volume":"11","author":"Brautigam","year":"2016","journal-title":"Nature Protocols"},{"key":"bib5","doi-asserted-by":"publisher","first-page":"674","DOI":"10.1016\/j.chembiol.2019.02.002","article-title":"Covalent modification and regulation of the nuclear receptor Nurr1 by a dopamine metabolite","volume":"26","author":"Bruning","year":"2019","journal-title":"Cell Chemical Biology"},{"key":"bib6","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1006\/jmbi.1997.1413","article-title":"Ligand- and DNA-induced dissociation of RXR tetramers","volume":"275","author":"Chen","year":"1998","journal-title":"Journal of Molecular Biology"},{"key":"bib7","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1038\/nature10383","article-title":"Antidiabetic actions of a non-agonist PPAR\u03b3 ligand blocking cdk5-mediated phosphorylation","volume":"477","author":"Choi","year":"2011","journal-title":"Nature"},{"key":"bib8","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1038\/nrneurol.2013.209","article-title":"Nurr1 in Parkinson disease -- from pathogenesis to therapeutic potential","volume":"9","author":"Decressac","year":"2013","journal-title":"Nature Reviews. 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