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 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.
Alvarez
Lautaro D
LD
Departamento de Quimica Organica, UMYMFOR-CONICET, Buenos Aires, Argentina.
Martí
Marcelo A
MA
Veleiro
Adriana S
AS
Presman
Diego M
DM
Estrin
Darío A
DA
Pecci
Adalí
A
Burton
Gerardo
G
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
C108699:21-hydroxy-6,19-oxidoprogesterone; D008024:Ligands; D011965:Receptors, Glucocorticoid; D011374:Progesterone; D003907:Dexamethasone