Exploring the Molecular Basis of Action of the Passive Antiglucocorticoid 21-Hydroxy-6,19-epoxyprogesterone

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• 作者：Lautaro D. Á ; lvarez ; Marcelo A. Martí ; Adriana S. Veleiro ; Diego M. Presman ; Darí ; o A. Estrin ; Adalí ; Pecci ; Gerardo Burton
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：March 13, 2008
• 年：2008
• 卷：51
• 期：5
• 页码：1352 - 1360
• 全文大小：1871K
• 年卷期：v.51,no.5(March 13, 2008)
• ISSN：1520-4804

文摘

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.