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Stapled peptide in complex with transcription factor NF-Y

Vreede, J. ; Ilie, Ioana M. ; Hennig, Sven ; Grossmann, Tom N. ; Bigiotti, Carlo

University of Amsterdam / Amsterdam University of Applied Sciences 2024

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  • Título:
    Stapled peptide in complex with transcription factor NF-Y
  • Autor: Vreede, J. ; Ilie, Ioana M. ; Hennig, Sven ; Grossmann, Tom N. ; Bigiotti, Carlo
  • Assuntos: Chemistry
  • Descrição: Transcription factors (TFs) play a central role in gene regulation, and their malfunction can result in a plethora of severe diseases. TFs are therefore interesting therapeutic targets, but their involvement in protein-protein interaction networks and the frequent lack of well-defined binding pockets render them challenging targets for classical small molecules. As an alternative, peptide-based scaffolds have proven useful, in particular with an α-helical active conformation. Peptide-based strategies often require extensive structural optimization efforts, which could benefit from a more detailed understanding of the dynamics in inhibitor/protein interactions. In this study, we investigate how truncated stapled α‑helical peptides interact with the transcription factor Nuclear Factor‑Y (NF-Y). We identified a 13-mer minimal binding core region, for which two crystal structures with an altered C-terminal peptide conformation when bound to NF-Y were obtained. Subsequent molecular dynamics simulations confirmed that the C-terminal part of the stapled peptide is indeed relatively flexible while still showing defined interactions with NF-Y. Our findings highlight the importance of flexibility in the bound state of peptides which can contribute to overall binding affinity.
  • Editor: University of Amsterdam / Amsterdam University of Applied Sciences
  • Data de criação/publicação: 2024
  • Idioma: Inglês
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  • Realização: ABCD-USP USP   Logos de Redes Sociais: Freepik

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