Modulators of the structural dynamics of the retinoid X receptor to reveal receptor function
| Autor: | Efrén O. Pérez, Oliver Hirsch, Hinrich Gronemeyer, Pierre Germain, William Bourguet, Fabio Manzo, Catherine A. Royer, Géraldine Lemaire, Fátima Rodríguez-Barrios, Angel R. de Lera, Virginie Nahoum, Sabrina Kammerer |
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| Přispěvatelé: | Centre de Biochimie Structurale [Montpellier] (CBS), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Instituto de Quimica de Sao Carlos, Universidade de São Paulo (USP), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Signalisation hormonale environnement et cancer, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Rok vydání: | 2007 |
| Předmět: |
Models
Molecular Coumaric Acids Tetrahydronaphthalenes Computational biology Retinoid X receptor Biology Ligands Cell Line Mice 03 medical and health sciences Liver X receptor beta 0302 clinical medicine Coactivator Animals Cell Proliferation 030304 developmental biology 0303 health sciences Pregnane X receptor Multidisciplinary Retinoid X receptor alpha [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry Molecular Biology/Molecular biology Biological Sciences Retinoid X receptor gamma Protein Structure Tertiary 3. Good health Retinoid X Receptors Biochemistry Nuclear receptor 030220 oncology & carcinogenesis Retinoid X receptor beta Protein Binding |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America Proceedings of the National Academy of Sciences of the United States of America, National Academy of Sciences, 2007, 104 (44), pp.17323-8. ⟨10.1073/pnas.0705356104⟩ |
| ISSN: | 0027-8424 1091-6490 |
| DOI: | 10.1073/pnas.0705356104⟩ |
| Popis: | Retinoid X receptors (RXRα, -β, and -γ) occupy a central position in the nuclear receptor superfamily, because they form heterodimers with many other family members and hence are involved in the control of a variety of (patho)physiologic processes. Selective RXR ligands, referred to as rexinoids, are already used or are being developed for cancer therapy and have promise for the treatment of metabolic diseases. However, important side effects remain associated with existing rexinoids. Here we describe the rational design and functional characterization of a spectrum of RXR modulators ranging from partial to pure antagonists and demonstrate their utility as tools to probe the implication of RXRs in cell biological phenomena. One of these ligands renders RXR activity particularly sensitive to coactivator levels and has the potential to act as a cell-specific RXR modulator. A combination of crystallographic and fluorescence anisotropy studies reveals the molecular details accounting for the agonist-to-antagonist transition and provides direct experimental evidence for a correlation between the pharmacological activity of a ligand and its impact on the structural dynamics of the activation helix H12. Using RXR and its cognate ligands as a model system, our correlative analysis of 3D structures and dynamic data provides an original view on ligand actions and enables the establishment of mechanistic concepts, which will aid in the development of selective nuclear receptor modulators. |
| Databáze: | OpenAIRE |
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