title: Identification of ligand-selective peptide antagonists of the mineralocorticoid receptor using phage display.
abstract: The mineralocorticoid receptor (MR) is a member of the nuclear receptor superfamily. Pathological activation of the MR causes cardiac fibrosis and heart failure, but clinical use of MR antagonists is limited by the renal side effect of hyperkalemia. The glucocorticoid cortisol binds the MR with equivalent affinity to that of the mineralocorticoids aldosterone and deoxycorticosterone. In nonepithelial tissues, including the myocardium, which do not express the cortisol-inactivating enzyme 11β hydroxysteroid dehydrogenase 2, cortisol has been implicated in the activation of MR. The mechanisms for ligand- and tissue-specific actions of the MR are undefined. Over the past decade, it has become clear that coregulator proteins are critical for nuclear receptor-mediated gene expression. A subset of these coregulators may confer specificity to MR-mediated responses. To evaluate whether different physiological ligands can induce distinct MR conformations that underlie differential coregulator recruitment and ligand-specific gene regulation, we utilized phage display technology to screen 10(8) 19mer peptides for their interaction with the MR in the presence of agonist ligands. We identified ligand-selective MR-interacting peptides that acted as potent antagonists of MR-mediated transactivation. This represents a novel mechanism of MR antagonism that may be manipulated in the rational design of a ligand- or tissue-selective MR modulator to treat diseases like heart failure without side effects such as hyperkalemia.
authors.affiliation: Prince Henry's Institute of Medical Research, Clayton, Victoria 3168, Australia.
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.forename: Ching-yi
authors.initials: CY
authors.lastname: Chang
authors.forename: Rachid
authors.initials: R
authors.lastname: Safi
authors.forename: James
authors.initials: J
authors.lastname: Morgan
authors.forename: Donald P
authors.initials: DP
authors.lastname: McDonnell
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Fuller
authors.forename: Colin D
authors.initials: CD
authors.lastname: Clyne
authors.forename: Morag J
authors.initials: MJ
authors.lastname: Young
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D017104:Bacteriophage M13; D002460:Cell Line; D016384:Consensus Sequence; D006801:Humans; D008024:Ligands; D000451:Mineralocorticoid Receptor Antagonists; D019151:Peptide Library; D010455:Peptides / Q000032:analysis* / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D018161:Receptors, Mineralocorticoid / Q000819:agonists / Q000737:chemistry; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D008024:Ligands; D000451:Mineralocorticoid Receptor Antagonists; D019151:Peptide Library; D010455:Peptides; D018161:Receptors, Mineralocorticoid