The human orphan nuclear receptor tailless (TLX, NR2E1) is druggable.
Nuclear receptors (NRs) are an important group of ligand-dependent transcriptional factors. Presently, no natural or synthetic ligand has been identified for a large group of orphan NRs. Small molecules to target these orphan NRs will provide unique resources for uncovering regulatory systems that i...
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doaj-137a4a00219b404e842bee770fbb9ed82020-11-25T01:14:51ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0196e9944010.1371/journal.pone.0099440The human orphan nuclear receptor tailless (TLX, NR2E1) is druggable.Cindy BenodRosa VillagomezCarly S FilgueiraPeter K HwangPaul G LeonardGuillaume Poncet-MontangeSenapathy RajagopalanRobert J FletterickJan-Åke GustafssonPaul WebbNuclear receptors (NRs) are an important group of ligand-dependent transcriptional factors. Presently, no natural or synthetic ligand has been identified for a large group of orphan NRs. Small molecules to target these orphan NRs will provide unique resources for uncovering regulatory systems that impact human health and to modulate these pathways with drugs. The orphan NR tailless (TLX, NR2E1), a transcriptional repressor, is a major player in neurogenesis and Neural Stem Cell (NSC) derived brain tumors. No chemical probes that modulate TLX activity are available, and it is not clear whether TLX is druggable. To assess TLX ligand binding capacity, we created homology models of the TLX ligand binding domain (LBD). Results suggest that TLX belongs to an emerging class of NRs that lack LBD helices α1 and α2 and that it has potential to form a large open ligand binding pocket (LBP). Using a medium throughput screening strategy, we investigated direct binding of 20,000 compounds to purified human TLX protein and verified interactions with a secondary (orthogonal) assay. We then assessed effects of verified binders on TLX activity using luciferase assays. As a result, we report identification of three compounds (ccrp1, ccrp2 and ccrp3) that bind to recombinant TLX protein with affinities in the high nanomolar to low micromolar range and enhance TLX transcriptional repressive activity. We conclude that TLX is druggable and propose that our lead compounds could serve as scaffolds to derive more potent ligands. While our ligands potentiate TLX repressive activity, the question of whether it is possible to develop ligands to de-repress TLX activity remains open.http://europepmc.org/articles/PMC4060991?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Cindy Benod Rosa Villagomez Carly S Filgueira Peter K Hwang Paul G Leonard Guillaume Poncet-Montange Senapathy Rajagopalan Robert J Fletterick Jan-Åke Gustafsson Paul Webb |
spellingShingle |
Cindy Benod Rosa Villagomez Carly S Filgueira Peter K Hwang Paul G Leonard Guillaume Poncet-Montange Senapathy Rajagopalan Robert J Fletterick Jan-Åke Gustafsson Paul Webb The human orphan nuclear receptor tailless (TLX, NR2E1) is druggable. PLoS ONE |
author_facet |
Cindy Benod Rosa Villagomez Carly S Filgueira Peter K Hwang Paul G Leonard Guillaume Poncet-Montange Senapathy Rajagopalan Robert J Fletterick Jan-Åke Gustafsson Paul Webb |
author_sort |
Cindy Benod |
title |
The human orphan nuclear receptor tailless (TLX, NR2E1) is druggable. |
title_short |
The human orphan nuclear receptor tailless (TLX, NR2E1) is druggable. |
title_full |
The human orphan nuclear receptor tailless (TLX, NR2E1) is druggable. |
title_fullStr |
The human orphan nuclear receptor tailless (TLX, NR2E1) is druggable. |
title_full_unstemmed |
The human orphan nuclear receptor tailless (TLX, NR2E1) is druggable. |
title_sort |
human orphan nuclear receptor tailless (tlx, nr2e1) is druggable. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2014-01-01 |
description |
Nuclear receptors (NRs) are an important group of ligand-dependent transcriptional factors. Presently, no natural or synthetic ligand has been identified for a large group of orphan NRs. Small molecules to target these orphan NRs will provide unique resources for uncovering regulatory systems that impact human health and to modulate these pathways with drugs. The orphan NR tailless (TLX, NR2E1), a transcriptional repressor, is a major player in neurogenesis and Neural Stem Cell (NSC) derived brain tumors. No chemical probes that modulate TLX activity are available, and it is not clear whether TLX is druggable. To assess TLX ligand binding capacity, we created homology models of the TLX ligand binding domain (LBD). Results suggest that TLX belongs to an emerging class of NRs that lack LBD helices α1 and α2 and that it has potential to form a large open ligand binding pocket (LBP). Using a medium throughput screening strategy, we investigated direct binding of 20,000 compounds to purified human TLX protein and verified interactions with a secondary (orthogonal) assay. We then assessed effects of verified binders on TLX activity using luciferase assays. As a result, we report identification of three compounds (ccrp1, ccrp2 and ccrp3) that bind to recombinant TLX protein with affinities in the high nanomolar to low micromolar range and enhance TLX transcriptional repressive activity. We conclude that TLX is druggable and propose that our lead compounds could serve as scaffolds to derive more potent ligands. While our ligands potentiate TLX repressive activity, the question of whether it is possible to develop ligands to de-repress TLX activity remains open. |
url |
http://europepmc.org/articles/PMC4060991?pdf=render |
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