Targeted Inhibition of the NCOA1/STAT6 Protein-Protein Interaction

Yeongju Lee, Heeseok Yoon, Sung Min Hwang, Min Kyung Shin, Ji Hoon Lee, Misook Oh, Sin Hyeog Im, Jaeyoung Song, Hyun Suk Lim

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

The complex formation between transcription factors (TFs) and coactivator proteins is required for transcriptional activity, and thus disruption of aberrantly activated TF/coactivator interactions could be an attractive therapeutic strategy. However, modulation of such protein-protein interactions (PPIs) has proven challenging. Here we report a cell-permeable, proteolytically stable, stapled helical peptide directly targeting nuclear receptor coactivator 1 (NCOA1), a coactivator required for the transcriptional activity of signal transducer and activator of transcription 6 (STAT6). We demonstrate that this stapled peptide disrupts the NCOA1/STAT6 complex, thereby repressing STAT6-mediated transcription. Furthermore, we solved the first crystal structure of a stapled peptide in complex with NCOA1. The stapled peptide therefore represents an invaluable chemical probe for understanding the precise role of the NCOA1/STAT6 interaction and an excellent starting point for the development of a novel class of therapeutic agents.

Original languageEnglish (US)
Pages (from-to)16056-16059
Number of pages4
JournalJournal of the American Chemical Society
Volume139
Issue number45
DOIs
StatePublished - Nov 15 2017
Externally publishedYes

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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    Lee, Y., Yoon, H., Hwang, S. M., Shin, M. K., Lee, J. H., Oh, M., Im, S. H., Song, J., & Lim, H. S. (2017). Targeted Inhibition of the NCOA1/STAT6 Protein-Protein Interaction. Journal of the American Chemical Society, 139(45), 16056-16059. https://doi.org/10.1021/jacs.7b08972