Artículo

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" (2008) Journal of Medicinal Chemistry. 51(5):1352-1360
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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-6,190P resides, at least in part, in the incapacity of the GR-21OH-6,19OP complex to dimerize. © 2008 American Chemical Society.

Registro:

Documento: Artículo
Título:Exploring the molecular basis of action of the passive antiglucocorticoid 21-hydroxy-6,19-epoxyprogesterone
Autor:Álvarez, L.D.; Martí, M.A.; Veleiro, A.S.; Presman, D.M.; Estrin, D.A.; Pecci, A.; Burton, G.
Filiación:Departamento de Química Orgánica/UMYMFOR-CONICET, Universidad de Buenos Aires, Pabellón 2, Buenos Aires CI428EGA, Argentina
Departamento de Quimica Inorganica, Analitica Y Quimica Fisica/INQUIMAE-CONICET, Universidad de Buenos Aires, Pabellón 2, Buenos Aires CI428EGA, Argentina
Departamento de Química Biológica/IFIBYNE-CONICET, Universidad de Buenos Aires, Pabellón 2, Buenos Aires CI428EGA, Argentina
Palabras clave: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)
Año:2008
Volumen:51
Número:5
Página de inicio:1352
Página de fin:1360
DOI: http://dx.doi.org/10.1021/jm800007w
Título revista:Journal of Medicinal Chemistry
Título revista abreviado:J. Med. Chem.
ISSN:00222623
CODEN:JMCMA
CAS:dexamethasone, 50-02-2; 21-hydroxy-6,19-oxidoprogesterone; Dexamethasone, 50-02-2; Ligands; Progesterone, 57-83-0; Receptors, Glucocorticoid
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00222623_v51_n5_p1352_Alvarez

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Citas:

---------- APA ----------
Álvarez, L.D., Martí, M.A., Veleiro, A.S., Presman, D.M., Estrin, D.A., Pecci, A. & Burton, G. (2008) . Exploring the molecular basis of action of the passive antiglucocorticoid 21-hydroxy-6,19-epoxyprogesterone. Journal of Medicinal Chemistry, 51(5), 1352-1360.
http://dx.doi.org/10.1021/jm800007w
---------- CHICAGO ----------
Álvarez, L.D., Martí, M.A., Veleiro, A.S., Presman, D.M., Estrin, D.A., Pecci, A., et al. "Exploring the molecular basis of action of the passive antiglucocorticoid 21-hydroxy-6,19-epoxyprogesterone" . Journal of Medicinal Chemistry 51, no. 5 (2008) : 1352-1360.
http://dx.doi.org/10.1021/jm800007w
---------- MLA ----------
Álvarez, L.D., Martí, M.A., Veleiro, A.S., Presman, D.M., Estrin, D.A., Pecci, A., et al. "Exploring the molecular basis of action of the passive antiglucocorticoid 21-hydroxy-6,19-epoxyprogesterone" . Journal of Medicinal Chemistry, vol. 51, no. 5, 2008, pp. 1352-1360.
http://dx.doi.org/10.1021/jm800007w
---------- VANCOUVER ----------
Álvarez, L.D., Martí, M.A., Veleiro, A.S., Presman, D.M., Estrin, D.A., Pecci, A., et al. Exploring the molecular basis of action of the passive antiglucocorticoid 21-hydroxy-6,19-epoxyprogesterone. J. Med. Chem. 2008;51(5):1352-1360.
http://dx.doi.org/10.1021/jm800007w