[Corticosteroid hormones: mechanisms involved in the recognition of aldosterone by mineralocorticoid receptors].

Aldosterone and cortisol, the major mineralocorticoid and glucocorticoid hormones in humans, are structurally very closed. Both hormones bind to the mineralocorticoid receptor (MR) with the same affinity. Nevertheless MR is preferentially activated by aldosterone, suggesting that the binding of these two hormones to MR involved some distinct contacts. We constructed a tridimensional model of the ligand-binding domain of the human MR, by taking as a template the structural data of the retinoid receptor associated with its ligand. The MR model allowed the identification of several residues involved in the interaction with aldosterone and cortisol. The residues Gln 776 and Arg 817 make hydrogen bonds with the 3-keto function and the residue Asn 770 with the C21-hydroxyl group. Analyses of the wild type and mutant MRs activities in response to corticosteroids bearing hydroxyl groups at various steroid skeleton position led to the following conclusions: 1) the interaction between the residue Asn 770 and the C21-hydroxyl group of corticosteroids is determinant for stabilizing the active MR conformation and 2) the stability of this conformation is enhanced by the 11-18 hemiketal group of aldosterone whereas it is decreased by the 11 beta- and 17 alpha-hydroxyl groups of cortisol. These results are discussed in the light of a model for the MR activation process.