title: Identification of steroid ligands able to inactivate the mineralocorticoid receptor harboring the S810L mutation responsible for a severe form of hypertension.
abstract: The ability of steroid ligands to inactivate the human mineralocorticoid receptor (MR(WT)) 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 MR(WT), have been shown to activate a mutant receptor (MR(L810)) 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 MR(WT) antagonists within the ligand-binding cavity is modified in such a way that they can activate the mutant MR(L810). The results from biochemical studies also revealed that 5alpha-pregnan-20-one, 4,9-androstadiene-3,17-dione and RU486, unable to bind MR(WT), acted as potent MR(L810) antagonists.
authors.affiliation: INSERM 478, Faculté de Médecine Xavier Bichat, B.P. 416, 16 rue Henri Huchard, 75870 Paris Cedex 18, France.
authors.forename: Grégory Maurice
authors.initials: GM
authors.lastname: Pinon
authors.forename: Jérôme
authors.initials: J
authors.lastname: Fagart
authors.forename: Anny
authors.initials: A
authors.lastname: Souque
authors.forename: Gilles
authors.initials: G
authors.lastname: Auzou
authors.forename: Alain
authors.initials: A
authors.lastname: Vandewalle
authors.forename: Marie-Edith
authors.initials: ME
authors.lastname: Rafestin-Oblin
mesh_terms: D019943:Amino Acid Substitution; D018360:Crystallography, X-Ray; D006801:Humans; D006973:Hypertension / Q000151:congenital / Q000235:genetics / Q000378:metabolism*; D007930:Leucine / Q000235:genetics; D008024:Ligands; D000451:Mineralocorticoid Receptor Antagonists; D009154:Mutation; D011485:Protein Binding / Q000235:genetics; D011487:Protein Conformation; D018161:Receptors, Mineralocorticoid / Q000737:chemistry / Q000235:genetics; D012694:Serine / Q000235:genetics; D013256:Steroids / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D000451:Mineralocorticoid Receptor Antagonists; D018161:Receptors, Mineralocorticoid; D013256:Steroids; D012694:Serine; D007930:Leucine