Specific hydroxylations determine selective corticosteroid recognition by human glucocorticoid and mineralocorticoid receptors

The ligand binding domains of the human mineralocorticoid receptor (hMR) an d glucocorticoid receptor (hGR) display a high sequence homology. Aldostero ne and cortisol, the major mineralocorticoid and glucocorticoid hormones, a re very closely related, leading to the cross-binding of these hormones to both receptors, The present study reports on the mechanism by which hMR and hGR are activated preferentially by their cognate hormones, We found that the ability of corticosteroids to stimulate the receptor's transactivation function is depending on the stability of the steroid-receptor complexes. I n the light of a hMR structural model we propose that contacts through the corticosteroid C21 hydroxyl group are sufficient to stabilize hMR but not h GR and that additional contacts through the C11- and C17-hydroxyl groups ar e required for hGR. (C) 1999 Federation of European Biochemical Societies.