Preventing estrogen receptor action with dimer-interface peptides

Steroids
M R Yudt, S Koide

Abstract

The human estrogen receptor-alpha (hER) is a ligand-activated transcription factor that functions as a homodimer. We sought to further understand the molecular processes involved in dimerization, and to develop a reagent that may function as an antiestrogen independent of the ligand binding site. To this end, we designed a 16-residue 'dimer-interface' oligopeptide derived from the helical region of the hER which is directly involved in dimerization. This peptide, termed the I-box peptide, has a high helical propensity in aqueous solution. The I-box peptide blocks hER action by causing aggregation and precipitation of both the ligand-bound and apo-hER. This effect is dependent on the helical nature of the peptide. A single Ile to Pro mutation in the helical region of the I-box peptide significantly reduces the helical content and abolishes the precipitation activity. Furthermore, the peptide activity appears to be specific for the hER. The I-box peptide does not significantly affect other proteins or steroid receptors tested. A homologous peptide derived from the nuclear receptor RXRalpha dimer interface, and a LXXLL-containing peptide from the coactivator TIF2 have no detectable in vitro effect on hER function or solubility. Ou...Continue Reading

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Citations

Dec 26, 2002·Journal of Molecular Recognition : JMR·A V VeselovskyP Janssen
Oct 3, 2002·Nature Reviews. Drug Discovery·Susan R GeorgeSamuel P Lee
Sep 6, 2012·Endocrine Reviews·Bramanandam ManavathiRakesh Kumar
Nov 26, 2009·Molecular Endocrinology·Terry W MooreJohn A Katzenellenbogen
May 10, 2005·Journal of Cellular Physiology·Arianna Loregian, Giorgio Palù
Jan 25, 2013·Medicinal Research Reviews·Laura Caboni, David G Lloyd
Jul 28, 2016·Biochemical and Biophysical Research Communications·S ChakrabortyR V Rajnarayanan
May 16, 2002·The Journal of Biological Chemistry·Alan BerezovRamachandran Murali
Jul 4, 2012·Molecular Diversity·Sandipan ChakrabortyP K Biswas

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