Structural Basis of Spirolactone Recognition by the Mineralocorticoid Receptor.
From: INSERM U773, Centre de Recherche Biomédicale Bichat-Beaujon, Paris, France.
Molecular pharmacology
- Publish Date: Sep 2007
- ISSN: 0026-895X
- Volume: 72
- Issue: 3
- Pages: 563-71
- Medium: Print
- Language: English
- Citation (JAMA): Huyet Jessica, Pinon Grégory M, Fay Michel R, et al. Structural Basis of Spirolactone Recognition by the Mineralocorticoid Receptor.. Mol. Pharmacol. Sep 2007;72:563-71
Abstract
Spirolactones are potent antagonists of the mineralocorticoid receptor (MR), a ligand-induced transcription factor belonging to the nuclear receptor superfamily. Spirolactones are synthetic molecules characterized by the presence of a C17 gamma-lactone, which is responsible for their antagonist character. They harbor various substituents at several positions of the steroid skeleton that modulate their potency in ways that remain to be determined. This is particularly obvious for C7 substituents. The instability of antagonist-MR complexes makes them difficult to crystallize. We took advantage of the S810L activating mutation in MR (MR(S810L)), which increases the stability of ligand-MR complexes to crystallize the ligand-binding domain (LBD) of MR(S810L) associated with 7alpha-acetylthio-17beta-hydroxy-3-oxopregn-4-en-21-carboxylic acid gamma-lactone (SC9420), a spirolactone with a C7 thioacetyl group. The crystal structure makes it possible to identify the contacts between SC9420 and MR and to elucidate the role of Met852 in the mode of accommodation of the C7 substituent of SC9420. The transactivation activities of MR(S810L/Q776A), MR(S810L/R817A), and MR(S810L/N770A) reveal that the contacts between SC9420 and the Gln776 and Arg817 residues are crucial to maintaining MR(S810L) in its active state, whereas the contact between SC9420 and the Asn770 residue contributes only to the high affinity of SC9420 for MR. Moreover, docking experiments with other C7-substituted spirolactones revealed that the MR(S810L)-activating potency of spirolactones is linked to the ability of their C7 substituent to be accommodated in LBD. It is remarkable that the MR(S810L)-activating and MR(WT)-inactivating potencies of the C7-substituted spirolactones follow the same order, suggesting that the C7 substituent is accommodated in the same way in MR(S810L) and MR(WT). Thus, the MR(S810L) structure may provide a powerful tool for designing new, more effective, MR antagonists.
Mesh Headings (Keywords): Amino Acid Substitution, Arginine, Asparagine, Binding Sites, Cell Line, Crystallography, X-Ray, Glycine, Humans, Hydrogen Bonding, Kidney, Ligands, Models, Molecular, Molecular Structure, Protein Binding, Protein Structure, Tertiary, Receptors, Mineralocorticoid, Spironolactone, Structure-Activity Relationship, Time Factors, Trans-Activation (Genetics), Transfection
Check for Full Text / PubMed Unique Identifier (PMID): 17569793
This abstract is part of PubMed, a service of the U.S. National Library of Medicine. PubMed includes more than 17 million citations from MEDLINE and other life science journals for biomedical articles. See Copyright and Disclaimers.
Linked medical terms appearing on this page are added by Healia to help readers find more information and are not part of the original PubMed document.
The data herein was last updated on July 8th, 2008 and may not reflect the most current and accurate data available from NLM.