title: Exploring the molecular basis of action of the passive antiglucocorticoid 21-hydroxy-6,19-epoxyprogesterone.
abstract: 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-6,19OP resides, at least in part, in the incapacity of the GR-21OH-6,19OP complex to dimerize.
authors.affiliation: Departamento de Quimica Organica, UMYMFOR-CONICET, Buenos Aires, Argentina.
authors.forename: Lautaro D
authors.initials: LD
authors.lastname: Alvarez
authors.forename: Marcelo A
authors.initials: MA
authors.lastname: Martí
authors.forename: Adriana S
authors.initials: AS
authors.lastname: Veleiro
authors.forename: Diego M
authors.initials: DM
authors.lastname: Presman
authors.forename: Darío A
authors.initials: DA
authors.lastname: Estrin
authors.forename: Adalí
authors.initials: A
authors.lastname: Pecci
authors.forename: Gerardo
authors.initials: G
authors.lastname: Burton
mesh_terms: D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D018360:Crystallography, X-Ray; D003907:Dexamethasone / Q000737:chemistry / Q000494:pharmacology; D019281:Dimerization; D017930:Genes, Reporter; D008024:Ligands; D051379:Mice; D018613:Microscopy, Confocal; D008958:Models, Molecular; D011374:Progesterone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D011401:Promoter Regions, Genetic; D021381:Protein Transport; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: C108699:21-hydroxy-6,19-oxidoprogesterone; D008024:Ligands; D011965:Receptors, Glucocorticoid; D011374:Progesterone; D003907:Dexamethasone