Constrained Peptides with Fine-Tuned Flexibility Inhibit NF-Y Transcription Factor Assembly

Sadasivam Jeganathan, Mathias Wendt, Sebastian Kiehstaller, Diego Brancaccio, Arne Kuepper, Nicole Pospiech, Alfonso Carotenuto, Ettore Novellino, Sven Hennig, Tom N. Grossmann

Research output: Contribution to JournalReview articleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)17351-17358
Number of pages8
JournalAngewandte Chemie - International Edition
Volume58
Issue number48
Early online date20 Sep 2019
DOIs
Publication statusPublished - 25 Nov 2019

Fingerprint

Transcription factors
Epitopes
Peptides
Transcription Factors
Conformations
Peptidomimetics
Methylation
Hydrocarbons
DNA
Tuning
Proteins

Bibliographical note

© 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.

Keywords

  • constrained peptides
  • peptide inhibitors
  • protein structure
  • protein–DNA interactions
  • protein–protein interactions

Cite this

Jeganathan, Sadasivam ; Wendt, Mathias ; Kiehstaller, Sebastian ; Brancaccio, Diego ; Kuepper, Arne ; Pospiech, Nicole ; Carotenuto, Alfonso ; Novellino, Ettore ; Hennig, Sven ; Grossmann, Tom N. / Constrained Peptides with Fine-Tuned Flexibility Inhibit NF-Y Transcription Factor Assembly. In: Angewandte Chemie - International Edition. 2019 ; Vol. 58, No. 48. pp. 17351-17358.
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Constrained Peptides with Fine-Tuned Flexibility Inhibit NF-Y Transcription Factor Assembly. / Jeganathan, Sadasivam; Wendt, Mathias; Kiehstaller, Sebastian; Brancaccio, Diego; Kuepper, Arne; Pospiech, Nicole; Carotenuto, Alfonso; Novellino, Ettore; Hennig, Sven; Grossmann, Tom N.

In: Angewandte Chemie - International Edition, Vol. 58, No. 48, 25.11.2019, p. 17351-17358.

Research output: Contribution to JournalReview articleAcademicpeer-review

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AU - Hennig, Sven

AU - Grossmann, Tom N.

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