Specific hydroxylations determine selective corticosteroid recognition by human glucocorticoid and mineralocorticoid receptors.
The ligand binding domains of the human mineralocorticoid receptor (hMR) and glucocorticoid receptor (hGR) display a high sequence homology. Aldosterone and cortisol, the major mineralocorticoid and glucocorticoid hormones, are 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. In the light of a hMR structural model we propose that contacts through the corticosteroid C21 hydroxyl group are sufficient to stabilize hMR but not hGR and that additional contacts through the C11- and C17-hydroxyl groups are required for hGR.
Hellal-Levy
C
C
INSERM U478, Faculté de Médecine Xavier Bichat, Institut Fédératif de Recherche 02, 16 rue Henri Huchard, P.O. Box 416, 75780, Paris, France.
Couette
B
B
Fagart
J
J
Souque
A
A
Gomez-Sanchez
C
C
Rafestin-Oblin
M
M
D000305:Adrenal Cortex Hormones / Q000494:pharmacology*; D000450:Aldosterone / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism; D001665:Binding Sites; D019556:COS Cells; D003907:Dexamethasone / Q000378:metabolism; D005938:Glucocorticoids / Q000378:metabolism; D006854:Hydrocortisone / Q000378:metabolism; D006900:Hydroxylation; D007700:Kinetics; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011487:Protein Conformation; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D018161:Receptors, Mineralocorticoid / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection
D000305:Adrenal Cortex Hormones; D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D000450:Aldosterone; D003907:Dexamethasone; D006854:Hydrocortisone