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Permissive NR-RXR activation is generally understood to operate through a classical pharmacological mechanism in which RXR agonist binding enhances coactivator recruitment to the heterodimer. However, we previously demonstrated that transcriptional activation of permissive Nurr1-RXR\u03b1 (NR4A2-NR2B1) heterodimers by an RXR ligand set, which included pharmacological RXR agonists and selective Nurr1-RXR\u03b1 agonists that function as antagonists of RXR\u03b1 homodimers, is explained by a non-classical activation mechanism involving ligand-binding domain (LBD) heterodimer dissociation (Yu et al., 2023). Here, we extend mechanistic ligand profiling of the same RXR ligand set to the evolutionarily related Nur77-RXR\u03b3 (NR4A1-NR2B3) heterodimer. Biochemical and NMR protein-protein interaction profiling, together with cellular transcription studies, indicate that activation of Nur77-RXR\u03b3 transcription by the RXR ligand set, which lacks selective Nur77-RXR\u03b3 agonists, is consistent with contributions from both classical pharmacological activation and LBD heterodimer dissociation. However, reanalysis of our previously published data for Nurr1-RXR\u03b1 revealed that inclusion of selective Nurr1-RXR\u03b1 agonists was essential for elucidating the LBD heterodimer dissociation mechanism. Together, our findings highlight the importance of using a more functionally diverse RXR ligand set to define the mechanism of Nur77-RXR\u03b3 activation and to further evaluate whether LBD heterodimer dissociation represents a shared activation mechanism among NR4A-RXR heterodimers relevant to neurodegenerative and inflammatory diseases.<\/jats:p>","DOI":"10.7554\/elife.106861","type":"journal-article","created":{"date-parts":[[2025,5,22]],"date-time":"2025-05-22T10:30:30Z","timestamp":1747909830000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.106861","source":"Crossref","is-referenced-by-count":3,"title":["Towards a unified molecular mechanism for ligand-dependent activation of NR4A-RXR 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