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Targeted Inhibition of the NCOA1/STAT6 Protein-Protein Interaction

Yeongju Lee1, Heeseok Yoon2, Sung-Min Hwang3

  • 1Department of Chemistry and Division of Advanced Material Science, Pohang University of Science and Technology (POSTECH) , Pohang 37673, South Korea.

Journal of the American Chemical Society
|November 2, 2017
PubMed

Insights

A novel stapled peptide disrupts the NCOA1/STAT6 complex, inhibiting STAT6-mediated transcription. This peptide serves as a chemical probe and a potential therapeutic lead for targeting protein-protein interactions.

Area of Science:

  • Molecular Biology
  • Structural Biology
  • Drug Discovery

Background:

  • Transcription factor (TF) and coactivator protein complex formation is crucial for transcriptional activity.
  • Targeting aberrant TF/coactivator interactions presents a therapeutic strategy, but modulating protein-protein interactions (PPIs) is challenging.

Purpose of the Study:

  • To develop a cell-permeable, stable peptide targeting nuclear receptor coactivator 1 (NCOA1).
  • To investigate the disruption of the NCOA1/STAT6 complex and its effect on STAT6-mediated transcription.
  • To elucidate the structural basis of stapled peptide interaction with NCOA1.

Main Methods:

  • Design and synthesis of a stapled helical peptide targeting NCOA1.
  • Assessment of the peptide's ability to disrupt the NCOA1/STAT6 complex in cells.
  • Determination of the crystal structure of the stapled peptide in complex with NCOA1.

Main Results:

  • A cell-permeable, proteolytically stable stapled peptide was developed that targets NCOA1.
  • The stapled peptide successfully disrupted the NCOA1/STAT6 complex, repressing STAT6-mediated transcription.
  • The first crystal structure of a stapled peptide bound to NCOA1 was determined.

Conclusions:

  • The stapled peptide is an effective chemical probe for studying the NCOA1/STAT6 interaction.
  • This peptide represents a promising starting point for developing new therapeutics targeting PPIs.

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