The Human Orphan Nuclear Receptor Tailless (TLX, NR2E1) Is Druggable
| Autor: | G. Poncet-Montange, Senapathy Rajagopalan, Robert J. Fletterick, Jan-Åke Gustafsson, Cindy Benod, Carly S. Filgueira, Paul Webb, Paul G. Leonard, Peter K. Hwang, Rosa Villagomez |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Models
Molecular Transcription Genetic Druggability lcsh:Medicine Receptors Cytoplasmic and Nuclear Plasma protein binding Ligands Biochemistry Intracellular Receptors Piperazines COUP Transcription Factor II 0302 clinical medicine Genes Reporter Basic Cancer Research Drug Discovery Medicine and Health Sciences Biomacromolecule-Ligand Interactions lcsh:Science 0303 health sciences Multidisciplinary Cancer Drug Discovery Ligand (biochemistry) Orphan Nuclear Receptors Cell biology Oncology Research Article Biotechnology Protein Binding Transcriptional Activation Drug Research and Development Molecular Sequence Data Biophysics Biology 03 medical and health sciences Inhibitory Concentration 50 Chemical Biology Estrogen Receptor beta Humans Luciferase Amino Acid Sequence Binding site Transcription factor 030304 developmental biology Luciferases Renilla Pharmacology Binding Sites Retinoid X Receptor alpha Retinoid X receptor alpha lcsh:R Biology and Life Sciences Proteins Molecular biology Biochemical Activity Nuclear receptor Dydrogesterone Pyrazoles lcsh:Q 030217 neurology & neurosurgery HeLa Cells |
| Zdroj: | PLoS ONE PLoS ONE, Vol 9, Iss 6, p e99440 (2014) |
| ISSN: | 1932-6203 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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