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Identification of ligand-selective peptide antagonists of the mineralocorticoid receptor using phage display.

Publication ,  Journal Article
Yang, J; Chang, C-Y; Safi, R; Morgan, J; McDonnell, DP; Fuller, PJ; Clyne, CD; Young, MJ
Published in: Mol Endocrinol
January 2011

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.

Duke Scholars

Published In

Mol Endocrinol

DOI

EISSN

1944-9917

Publication Date

January 2011

Volume

25

Issue

1

Start / End Page

32 / 43

Location

United States

Related Subject Headings

  • Transcriptional Activation
  • Receptors, Mineralocorticoid
  • Protein Binding
  • Promoter Regions, Genetic
  • Peptides
  • Peptide Library
  • Mineralocorticoid Receptor Antagonists
  • Ligands
  • Humans
  • Endocrinology & Metabolism
 

Citation

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MLA
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Yang, J., Chang, C.-Y., Safi, R., Morgan, J., McDonnell, D. P., Fuller, P. J., … Young, M. J. (2011). Identification of ligand-selective peptide antagonists of the mineralocorticoid receptor using phage display. Mol Endocrinol, 25(1), 32–43. https://doi.org/10.1210/me.2010-0193
Yang, Jun, Ching-yi Chang, Rachid Safi, James Morgan, Donald P. McDonnell, Peter J. Fuller, Colin D. Clyne, and Morag J. Young. “Identification of ligand-selective peptide antagonists of the mineralocorticoid receptor using phage display.Mol Endocrinol 25, no. 1 (January 2011): 32–43. https://doi.org/10.1210/me.2010-0193.
Yang J, Chang C-Y, Safi R, Morgan J, McDonnell DP, Fuller PJ, et al. Identification of ligand-selective peptide antagonists of the mineralocorticoid receptor using phage display. Mol Endocrinol. 2011 Jan;25(1):32–43.
Yang, Jun, et al. “Identification of ligand-selective peptide antagonists of the mineralocorticoid receptor using phage display.Mol Endocrinol, vol. 25, no. 1, Jan. 2011, pp. 32–43. Pubmed, doi:10.1210/me.2010-0193.
Yang J, Chang C-Y, Safi R, Morgan J, McDonnell DP, Fuller PJ, Clyne CD, Young MJ. Identification of ligand-selective peptide antagonists of the mineralocorticoid receptor using phage display. Mol Endocrinol. 2011 Jan;25(1):32–43.

Published In

Mol Endocrinol

DOI

EISSN

1944-9917

Publication Date

January 2011

Volume

25

Issue

1

Start / End Page

32 / 43

Location

United States

Related Subject Headings

  • Transcriptional Activation
  • Receptors, Mineralocorticoid
  • Protein Binding
  • Promoter Regions, Genetic
  • Peptides
  • Peptide Library
  • Mineralocorticoid Receptor Antagonists
  • Ligands
  • Humans
  • Endocrinology & Metabolism