PT  - JOURNAL ARTICLE
AU  - Paola Munoz-Tello
AU  - Hua Lin
AU  - Pasha Khan
AU  - Ian Mitchelle S. de Vera
AU  - Theodore M. Kamenecka
AU  - Douglas J. Kojetin
TI  - Assessment of NR4A Ligands that Directly Bind and Modulate the Orphan Nuclear Receptor Nurr1
AID  - 10.1101/2020.05.22.109017
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.05.22.109017
4099  - http://biorxiv.org/content/early/2020/05/25/2020.05.22.109017.short
4100  - http://biorxiv.org/content/early/2020/05/25/2020.05.22.109017.full
AB  - Nurr1/NR4A2 is an orphan nuclear receptor transcription factor implicated as a potential drug target for neurological disorders including Alzheimer’s and Parkinson’s diseases. Previous studies identified small molecule modulators of NR4A nuclear receptors including Nurr1 and Nur77/NR4A1; it remains unclear whether these ligands affect Nurr1 through direct binding or indirect non-binding mechanisms. We assessed a panel of twelve ligands reported to affect NR4A activity for Nurr1-dependent and Nurr1-independent transcriptional effects and binding to the Nurr1 ligand-binding domain (LBD). Most of the NR4A ligands show Nurr1-independent effects on transcription in a cell type-specific manner, suggesting they may function through binding to effector proteins whose downstream activities influence Nurr1 function. Protein NMR spectroscopy structural footprinting data show that 4-amino-7-chloroquinoline derivatives (amodiaquine and chloroquine) and cytosporone B directly bind the Nurr1 LBD. In contrast, other NR4A ligands including commercially available compounds such as C-DIM12, celastrol, camptothecin, IP7e, isoalantolactone, and TMPA do not bind the Nurr1 LBD. Interestingly, previous crystal structures indicate that cytosporone B analogs bind to surface pockets in the Nur77 LBD, but protein NMR data indicate cytosporone B likely binds to the Nurr1 orthosteric pocket. These findings should influence medicinal chemistry efforts that desire to optimize Nurr1-binding ligands as opposed to ligands that function through binding to Nurr1 effector proteins.Competing Interest StatementThe authors have declared no competing interest.