Identitication of steroid ligands able to inactivate the mineralocorticoid receptor harboring the S810L mutation responsible for a severe form of hypertension

The ability of steroid ligands to inactivate the human mineralocorticoid receptor (MRWT) has been shown to be due to their inability to contact Asn770. a residue of the H3 helix involved in stabilizing contacts with the H11-H12 loop region. However, all steroid ligands that display antagonist properties when bound to MRWT, have been shown to activate a mutant receptor (MRL810) associated with a severe form of hypertension. Biochemical studies revealed that S810L mutation induces a change in the receptor conformation and increases the steroid-receptor complexes stability. From a three-dimensional model of the MR ligand-binding domain, it is likely that the S810L mutation causes a steric hindrance between the side chains of Leu810 (H5) and Gln776 (H3) that provokes a bending of the H3 helix. As a consequence, the positioning of MRWT antagonists within the ligand-binding cavity is modified in such a way that they can activate the mutant MRL810. The results from biochemical studies also revealed that 5alpha-pregnan-20-one, 4,9-androstadiene-3,17-dione and RU486, unable to bind MRWT, acted as potent MRL810 antagonists. (C) 2003 Elsevier Ireland Ltd. All rights reserved.