The Orphan Nuclear Receptor TLX Is a Receptor for Synthetic and Natural Retinoids.

Autor:	Griffett K; Center for Clinical Pharmacology, Washington University School of Medicine and St. Louis College of Pharmacy, St. Louis, MO 63110, USA., Bedia-Diaz G; Center for Clinical Pharmacology, Washington University School of Medicine and St. Louis College of Pharmacy, St. Louis, MO 63110, USA., Hegazy L; Center for Clinical Pharmacology, Washington University School of Medicine and St. Louis College of Pharmacy, St. Louis, MO 63110, USA., de Vera IMS; Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, MO 63104, USA., Wanninayake US; Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, MO 63104, USA., Billon C; Center for Clinical Pharmacology, Washington University School of Medicine and St. Louis College of Pharmacy, St. Louis, MO 63110, USA., Koelblen T; Center for Clinical Pharmacology, Washington University School of Medicine and St. Louis College of Pharmacy, St. Louis, MO 63110, USA., Wilhelm ML; Division of Biology and Biomedical Sciences, Washington University, St. Louis, MO 63110, USA., Burris TP; Center for Clinical Pharmacology, Washington University School of Medicine and St. Louis College of Pharmacy, St. Louis, MO 63110, USA; Division of Biology and Biomedical Sciences, Washington University, St. Louis, MO 63110, USA. Electronic address: burristhomas@wustl.edu.
Jazyk:	angličtina
Zdroj:	Cell chemical biology [Cell Chem Biol] 2020 Oct 15; Vol. 27 (10), pp. 1272-1284.e4. Date of Electronic Publication: 2020 Aug 06.
DOI:	10.1016/j.chembiol.2020.07.013
Abstrakt:	TLX is an orphan nuclear receptor that plays a critical role in both embryonic and adult neurogenesis, as well in the pathogenesis of glioblastomas. TLX functions predominately as a transcriptional repressor, but no natural ligands or high-affinity synthetic ligands have been identified. Here, we describe the identification of natural and synthetic retinoids as functional ligands for TLX. We identified potent synthetic retinoids that directly bind to TLX and either activate or inhibit its transcriptional repressor activity. Furthermore, we identified all-trans and 11-cis retinaldehyde (retinal), retinoids that play an essential role in the visual cycle, as the preferential natural retinoids that bind to and modulate the function of TLX. Molecular dynamics simulations followed by mutational analysis provided insight into the molecular basis of retinoid binding to TLX. Our data support the validity of TLX as a target for development of therapeutics to treat cognitive disorders and/or glioblastomas. Competing Interests: Declaration of Interests Authors declare no competing interests. (Copyright © 2020 Elsevier Ltd. All rights reserved.)
Databáze:	MEDLINE
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