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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todo:paper_00222623_v51_n5_p1352_Alvarez2023-10-03T14:30:16Z Exploring the molecular basis of action of the passive antiglucocorticoid 21-hydroxy-6,19-epoxyprogesterone Álvarez, L.D. Martí, M.A. Veleiro, A.S. Presman, D.M. Estrin, D.A. Pecci, A. Burton, G. 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) 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. Fil:Álvarez, L.D. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Martí, M.A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Veleiro, A.S. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Presman, D.M. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Estrin, D.A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Pecci, A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Burton, G. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_00222623_v51_n5_p1352_Alvarez |
institution |
Universidad de Buenos Aires |
institution_str |
I-28 |
repository_str |
R-134 |
collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
topic |
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) |
spellingShingle |
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) Álvarez, L.D. Martí, M.A. Veleiro, A.S. Presman, D.M. Estrin, D.A. Pecci, A. Burton, G. Exploring the molecular basis of action of the passive antiglucocorticoid 21-hydroxy-6,19-epoxyprogesterone |
topic_facet |
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) |
description |
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. |
format |
JOUR |
author |
Álvarez, L.D. Martí, M.A. Veleiro, A.S. Presman, D.M. Estrin, D.A. Pecci, A. Burton, G. |
author_facet |
Álvarez, L.D. Martí, M.A. Veleiro, A.S. Presman, D.M. Estrin, D.A. Pecci, A. Burton, G. |
author_sort |
Álvarez, L.D. |
title |
Exploring the molecular basis of action of the passive antiglucocorticoid 21-hydroxy-6,19-epoxyprogesterone |
title_short |
Exploring the molecular basis of action of the passive antiglucocorticoid 21-hydroxy-6,19-epoxyprogesterone |
title_full |
Exploring the molecular basis of action of the passive antiglucocorticoid 21-hydroxy-6,19-epoxyprogesterone |
title_fullStr |
Exploring the molecular basis of action of the passive antiglucocorticoid 21-hydroxy-6,19-epoxyprogesterone |
title_full_unstemmed |
Exploring the molecular basis of action of the passive antiglucocorticoid 21-hydroxy-6,19-epoxyprogesterone |
title_sort |
exploring the molecular basis of action of the passive antiglucocorticoid 21-hydroxy-6,19-epoxyprogesterone |
url |
http://hdl.handle.net/20.500.12110/paper_00222623_v51_n5_p1352_Alvarez |
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