Determinants of spironolactone binding specificity in the mineralocorticoid receptor.

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Rogerson FM, Yao YZ, Smith BJ, Dimopoulos N, Fuller PJ

Determinants of spironolactone binding specificity in the mineralocorticoid receptor.

J Mol Endocrinol. 2003 Dec;31(3):573-82.

PubMed ID

14664717 [ View in PubMed

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Abstract

Spironolactone is a mineralocorticoid receptor (MR) antagonist in clinical use. The compound has a very low affinity for the glucocorticoid receptor (GR). Determinants of binding specificity of spironolactone to the MR were investigated using chimeras created between the ligand-binding domains (LBDs) of the MR and the GR. These chimeras had previously been used to investigate aldosterone binding specificity to the MR. Spironolactone was able to compete strongly for [(3)H]-aldosterone and [(3)H]-dexamethasone binding to a chimera containing amino acids 804-874 of the MR, and weakly for [(3)H]-dexamethasone binding to a chimera containing amino acids 672-803 of the MR. Amino acids 804-874 were also critical for aldosterone binding specificity. Models of the MR LBD bound to aldosterone and spironolactone were created based on the crystal structure of the progesterone receptor LBD. The ligand-binding pocket of the MR LBD model consisted of 23 amino acids and was predominantly hydrophobic in nature. Analysis of this model in light of the experimental data suggested that spironolactone binding specificity is not governed by amino acids in the ligand-binding pocket.

DrugBank Data that Cites this Article

Drugs

Spironolactone

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Spironolactone	Glucocorticoid receptor	Protein	Humans	Unknown	Antagonist	Details
Spironolactone	Mineralocorticoid receptor	Protein	Humans	Yes	Antagonist	Details