| Autor: |
G, Auzou, J, Fagart, A, Souque, C, Hellal-Lvy, M, Wurtz J, D, Moras, E, Rafestin-Oblin M |
| Zdroj: |
Molecular Pharmacology; October 2000, Vol. 58 Issue: 4 p684-91, 8p |
| Abstrakt: |
Sequence analysis revealed a strong homology between the ligand-binding domain (LBD) of the human mineralocorticoid receptor (hMR) and glucocorticoid receptor (hGR). Nevertheless, steroids with bulky C11-substituents bind to hGR, unlike hMR. In this report, a mutant hMR, in which the residue Ala-773 facing the C11 steroid position was replaced by a glycine (A773G), was assayed for its capacity to bind steroids, to interact with receptor coactivators, and to stimulate transcription. The capacity of A773G to bind aldosterone and C11-substituted spirolactones was the same as that of the wild-type receptor. The agonist properties of aldosterone, as well as the antagonist feature of compounds bearing a 11beta-allenyl group and a C17-ketone function, remain unchanged. In contrast, C11-substituted steroids with a 17gamma-lactonic ring displayed antagonist properties with hMR and acted as potent agonists with A773G. An agonist-dependent hMR interaction with SRC-1 was observed for both the wild-type and the mutant receptors. The hMR activation process is discussed in the light of the hMR-LBD homology model based on the structural data of the human progesterone receptor LBD. |
| Databáze: |
Supplemental Index |
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