Synthetic peptides that specifically bind nuclear hormone receptors offer an alternative approach to small molecules for the modulation of receptor signaling and subsequent gene expression. Here we describe the design of a series of novel stapled peptides that bind the coactivator peptide site of estrogen receptors. Using a number of biophysical techniques, including crystal structure analysis of receptor-stapled peptide complexes, we describe in detail the molecular interactions and demonstrate that all-hydrocarbon staples modulate molecular recognition events. The findings have implications for the design of stapled peptides in general as the addition of the all-hydrocarbon staple not only conformationally restrains the peptide but can also affect the interactions of the peptide with hydrophobic protein surfaces.

Design and structure of stapled peptides binding to estrogen receptors

244th National Meeting (2012)

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