6QMS

NF-YB/C Heterodimer in Complex with NF-YA-derived Peptide Stabilized with C11-Hydrocarbon Linker

Summary for 6QMS

• Entry DOI: 10.2210/pdb6qms/pdb
• Descriptor: Nuclear transcription factor Y subunit alpha, Nuclear transcription factor Y subunit beta, Nuclear transcription factor Y subunit gamma, ... (4 entities in total)
• Functional Keywords: stapled peptide histone fold transcription factor, transcription
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 24570.77

Authors

Kiehstaller, S.,Jeganathan, S.,Pearce, N.M.,Wendt, M.,Grossmann, T.N.,Hennig, S. (deposition date: 2019-02-08, release date: 2019-10-02, Last modification date: 2024-11-06)

Primary citation

Jeganathan, S.,Wendt, M.,Kiehstaller, S.,Brancaccio, D.,Kuepper, A.,Pospiech, N.,Carotenuto, A.,Novellino, E.,Hennig, S.,Grossmann, T.N.
Constrained Peptides with Fine-Tuned Flexibility Inhibit NF-Y Transcription Factor Assembly.
Angew.Chem.Int.Ed.Engl., 58:17351-17358, 2019

PubMed Abstract: Protein complex formation depends on the interplay between preorganization and flexibility of the binding epitopes involved. The design of epitope mimetics typically focuses on stabilizing a particular bioactive conformation, often without considering conformational dynamics, which limits the potential of peptidomimetics against challenging targets such as transcription factors. We developed a peptide-derived inhibitor of the NF-Y transcription factor by first constraining the conformation of an epitope through hydrocarbon stapling and then fine-tuning its flexibility. In the initial set of constrained peptides, a single non-interacting α-methyl group was observed to have a detrimental effect on complex stability. Biophysical characterization revealed how this methyl group affects the conformation of the peptide in its bound state. Adaption of the methylation pattern resulted in a peptide that inhibits transcription factor assembly and subsequent recruitment to the target DNA.

PubMed: 31539186
DOI: 10.1002/anie.201907901

Experimental method

X-RAY DIFFRACTION (1.8 Å)