The Transcriptional Repressor Orphan Nuclear Receptor TLX Is Responsive to Xanthines

Faudone, Giuseppe; Kilu, Whitney; Ni, Xiaomin; Chaikuad, Apirat; Sreeramulu, Sridhar; Heitel, Pascal; Schwalbe, Harald; Knapp, Stefan; Schubert-Zsilavecz, Manfred; Heering, Jan und Merk, Daniel (2021): The Transcriptional Repressor Orphan Nuclear Receptor TLX Is Responsive to Xanthines. In: ACS Pharmacology & Translational Science, Bd. 4, Nr. 6: S. 1794-1807

Abstract

The orphan nuclear receptor tailless homologue (TLX) is expressed almost exclusively in neural stem cells acting as an essential factor for their survival and is hence considered as a promising drug target in neurodegeneration. However, few studies have characterized the roles of TLX due to the lack of ligands and limited functional understanding. Here, we identify xanthines including caffeine and istradefylline as TLX modulators that counteract the receptor's intrinsic repressor activity. Mutagenesis of residues lining a cavity within the TLX ligand binding domain altered the activity of these ligands, suggesting direct interactions with helix S. Using xanthines as tool compounds, we observed a ligand-sensitive recruitment of the co-repressor silencing mediator for retinoid or thyroid-hormone receptors, TLX homodimerization, and heterodimerization with the retinoid X receptor. These protein-protein interactions evolve as factors that modulate the TLX function and suggest an unprecedented role of TLX in directly repressing other nuclear receptors.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Chemie und Pharmazie > Department für Pharmazie - Zentrum für Pharmaforschung
• Themengebiete: 500 Naturwissenschaften und Mathematik > 540 Chemie
• Sprache: Englisch