Exploring the molecular basis of action of the passive antiglucocorticoid 21-hydroxy-6,19-epoxyprogesterone

21-Hydroxy-6,19-epoxyprogesterone (21OH-6,19OP) is a selective antiglucocorticoid that lacks the bulky substituent at C-11 found in active antagonists of the glucocorticoid receptor (GR). Ligand-free GR ligand-binding domain (LBD) and GR LBD complexed with 21OH-6,19OP or the agonist dexamethasone we...

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Detalles Bibliográficos
Autores principales: Álvarez, L.D., Martí, M.A., Veleiro, A.S., Presman, D.M., Estrin, D.A., Pecci, A., Burton, G.
Formato: JOUR
Materias:
21 hydroxy 6,19 epoxyprogesterone
dexamethasone
glucocorticoid antagonist
glucocorticoid receptor
homodimer
transcriptome
unclassified drug
animal cell
article
binding affinity
drug mechanism
gene activation
gene location
gene translocation
molecular dynamics
mouse
nonhuman
transactivation
Animals
Binding Sites
Cell Line
Cell Nucleus
Crystallography, X-Ray
Dexamethasone
Dimerization
Genes, Reporter
Ligands
Mice
Microscopy, Confocal
Models, Molecular
Progesterone
Promoter Regions (Genetics)
Protein Transport
Receptors, Glucocorticoid
Trans-Activation (Genetics)
Acceso en línea:http://hdl.handle.net/20.500.12110/paper_00222623_v51_n5_p1352_Alvarez
Aporte de:
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires
Descripción
Sumario:21-Hydroxy-6,19-epoxyprogesterone (21OH-6,19OP) is a selective antiglucocorticoid that lacks the bulky substituent at C-11 found in active antagonists of the glucocorticoid receptor (GR). Ligand-free GR ligand-binding domain (LBD) and GR LBD complexed with 21OH-6,19OP or the agonist dexamethasone were simulated during 6 ns using molecular dynamics. Results suggest that the time fluctuation and average position adopted by the H1-H3 loop affect the ability of GR LBD-21OH-6,19OP complex to homodimerize, a necessary step in transcriptome assembly. A nuclear localization and a transactivation experiment showed that, although 21OH-6,19OP activates the translocation of the GR, the nuclear complex is unable to induce the transcription of a reporter driven by a promoter, that requires binding to a GR homodimer to be activated. These findings support the hypothesis that the passive antagonist mode of action of 21OH-6,190P resides, at least in part, in the incapacity of the GR-21OH-6,19OP complex to dimerize. © 2008 American Chemical Society.

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