Identification 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 (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.
Pinon
Grégory Maurice
GM
INSERM 478, Faculté de Médecine Xavier Bichat, B.P. 416, 16 rue Henri Huchard, 75870 Paris Cedex 18, France.
Fagart
Jérôme
J
Souque
Anny
A
Auzou
Gilles
G
Vandewalle
Alain
A
Rafestin-Oblin
Marie-Edith
ME
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
D008024:Ligands; D000451:Mineralocorticoid Receptor Antagonists; D018161:Receptors, Mineralocorticoid; D013256:Steroids; D012694:Serine; D007930:Leucine