Molecular Basis for Ligand Activation of NR4A-RXR

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dc.contributor.advisorKojetin, Douglas J
dc.contributor.committeeChairSanders, Charles R
dc.creatorYu, Xiaoyu
dc.creator.orcid0000-0003-0549-9560
dc.date.accessioned2025-06-06T09:45:58Z
dc.date.created2025-05
dc.date.issued2025-01-06
dc.date.submittedMay 2025
dc.description.abstractTwo members of the orphan nuclear receptor (NR) NR4A family, Nurr1 and Nur77, are essential for the development, regulation, and maintenance of several important aspects of mammalian brain development and homeostasis and have been shown to be associated with pathological development and progression, including Parkinson’s disease (PD) and Alzheimer’s disease (AD). Although NRs are considered to be ligand-dependent transcription factors, Nurr1 and Nur77 are thought to function independent of binding an endogenous ligand that is produced and present in cells. It also remains unknown in the field whether there are functional endogenous ligands that bind to the ligand-binding domains (LBD) of Nurr1 and/or Nur77 via their putative canonical ligand-binding pocket, a region within the core of the LBD conserved across the NR superfamily where endogenous ligands bind to other NRs. An alternative way to target NR4A activity is through ligands that bind to the retinoid X receptor (RXR), which forms heterodimers with Nurr1 and Nur77. Interestingly, although RXR activates transcription of most NR-RXR heterodimers including PPARγ-RXRα, RXR heterodimerization represses Nurr1 and Nur77 transcription. Additionally, synthetic RXR ligands can activate transcription of Nurr1- and Nur77-RXR heterodimers and have been implicated in treating neurodegenerative disorders. However, the mechanism by which RXRα represses Nurr1 and Nur77 transcription, and the mechanism of action of ligands that activate NR4A-RXR transcription, remain poorly understood. Here, I use a multidisciplinary approach combining structural biology, biochemistry, biophysics, and molecular and cellular pharmacology approaches to characterize the structure of Nurr1-RXRα LBD heterodimer, which uncovered a novel structural mechanism of ligand-dependent activation of NR4A-RXR heterodimers: RXR ligands can function as allosteric protein-protein interaction inhibitors that bind to the canonical orthosteric ligand-binding pocket within the RXR LBD and influence NR4A-mediated transcription via heterodimer dissociation. This dissertation provides fundamental insights into the structural mechanisms governing NR4A-RXR heterodimer function and ligand-dependent activation, which may inform the development of targeted therapeutic strategies for PD, AD, and other aging-associated neurodegenerative disorders.
dc.format.mimetypeapplication/pdf
dc.identifier.urihttps://hdl.handle.net/1803/19750
dc.language.isoen
dc.subjectNMR spectroscopy
dc.subjectbiochemistry
dc.subjectbiophysics
dc.subjectchemical biology
dc.subjectligand binding
dc.subjectmolecular biophysics
dc.subjectnuclear receptors
dc.subjectprotein-protein interaction
dc.subjectstructural biology
dc.subjecttranscription factors
dc.titleMolecular Basis for Ligand Activation of NR4A-RXR
dc.typeThesis
dc.type.materialtext
local.embargo.lift2027-05-01
local.embargo.terms2027-05-01
thesis.degree.disciplineBiochemistry
thesis.degree.grantorVanderbilt University Graduate School
thesis.degree.levelDoctoral
thesis.degree.namePhD
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