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Vol. 58, Issue 4, 684-691, October 2000

A Single Amino Acid Mutation of Ala-773 in the Mineralocorticoid Receptor Confers Agonist Properties to 11beta -Substituted Spirolactones

Gilles Auzou,1 Jérôme Fagart,1 Anny Souque, Chantal Hellal-Lévy, Jean-Marie Wurtz, Dino Moras, and Marie-Edith Rafestin-Oblin

Institut National de la Santé et de la Recherche Médicale U439, Montpellier, France (G.A.); Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, CU de Strasbourg, France (J.F., J.-M.W., D.M.); and Institut National de la Santé et de la Recherche Médicale U478, Faculté de médecine Xavier Bichat, Institut Fédératif de Recherche 02, Paris, France (A.S., C.H.-L., M.-E.R.-O.)

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.

1 Considered jointly as first authors.

Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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