title: Structural determinants of ligand binding to the mineralocorticoid receptor.
abstract: The first and critical step in the mechanism of aldosterone action is its binding to the mineralocorticoid receptor (MR), a member of the nuclear receptor superfamily. Over the last 40 years, numerous studies have attempted to determine the structural determinants of ligand-binding to MR. An initial set of data showed that hsp90 is bound to the receptor via specific regions and maintains it in a ligand-binding competent state. Site-directed mutagenesis and functional studies guided by a 3D model of the MR ligand-binding domain (LBD) made it possible to identify the residues responsible for the high affinity and selectivity for aldosterone, and to characterize the mechanisms of MR activation and inactivation. The recent determination of the X-ray crystal structures of the LBD of the wild-type MR and MR(S810L), which is responsible for a familial form of hypertension, has made it possible to elucidate the peculiar mechanism of activation of MR(S810L) and established a clear structure/activity relationship for steroidal and non-steroidal MR antagonists.
authors.affiliation: INSERM U773, Centre de Recherche Biomédicale Bichat-Beaujon, CRB3, Paris, France.
authors.forename: Jessica
authors.initials: J
authors.lastname: Huyet
authors.forename: Grégory Maurice
authors.initials: GM
authors.lastname: Pinon
authors.forename: Michel Raymond
authors.initials: MR
authors.lastname: Fay
authors.forename: Marie-Edith
authors.initials: ME
authors.lastname: Rafestin-Oblin
authors.forename: Jérôme
authors.initials: J
authors.lastname: Fagart
mesh_terms: D000450:Aldosterone / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D018360:Crystallography, X-Ray; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008024:Ligands; D000451:Mineralocorticoid Receptor Antagonists; D008954:Models, Biological; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs / Q000502:physiology; D018161:Receptors, Mineralocorticoid / Q000819:agonists / Q000737:chemistry* / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D018841:HSP90 Heat-Shock Proteins; D008024:Ligands; D000451:Mineralocorticoid Receptor Antagonists; D018161:Receptors, Mineralocorticoid; D000450:Aldosterone