8QU4

NF-YB/C Heterodimer in Complex with a 13-mer NF-YA-derived Peptide Stabilized with C8-Hydrocarbon Linker in an alternative binding pose

Summary for 8QU4

• Entry DOI: 10.2210/pdb8qu4/pdb
• Descriptor: Nuclear transcription factor Y subunit alpha, Nuclear transcription factor Y subunit beta, Nuclear transcription factor Y subunit gamma, ... (6 entities in total)
• Functional Keywords: peptidometic inhibitor, transcription
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 24067.07

Authors

Arbore, F.,Durukan, C.,Klintrot, C.I.R.,Grossmann, T.N.,Hennig, S. (deposition date: 2023-10-13, release date: 2024-03-20, Last modification date: 2024-05-15)

Primary citation

Durukan, C.,Arbore, F.,Klintrot, R.,Bigiotti, C.,Ilie, I.M.,Vreede, J.,Grossmann, T.N.,Hennig, S.
Binding Dynamics of a Stapled Peptide Targeting the Transcription Factor NF-Y.
Chembiochem, 25:e202400020-e202400020, 2024

PubMed Abstract: 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.

PubMed: 38470946
DOI: 10.1002/cbic.202400020

Experimental method

X-RAY DIFFRACTION (1.38 Å)