8qu4

Publication Abstract from PubMed

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 alpha-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 alpha-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.

Binding Dynamics of a Stapled Peptide Targeting the Transcription Factor NF-Y.,Durukan C, Arbore F, Klintrot R, Bigiotti C, Ilie IM, Vreede J, Grossmann TN, Hennig S Chembiochem. 2024 May 2;25(9):e202400020. doi: 10.1002/cbic.202400020. Epub 2024 , Apr 2. PMID:38470946^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.