Constrained Peptides with Fine‐Tuned Flexibility Inhibit NF‐Y Transcription Factor Assembly
| Autor: | Mathias Wendt, Sven Hennig, Arne Kuepper, Nicole Pospiech, Diego Brancaccio, Sadasivam Jeganathan, Tom N. Grossmann, Ettore Novellino, Alfonso Carotenuto, Sebastian Kiehstaller |
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| Přispěvatelé: | Jeganathan, Sadasivam, Wendt, Mathia, Kiehstaller, Sebastian, Brancaccio, Diego, Kuepper, Arne, Pospiech, Nicole, Carotenuto, Alfonso, Novellino, Ettore, Hennig, Sven, Grossmann, Tom N |
| Rok vydání: | 2019 |
| Předmět: |
Protein Conformation
Peptidomimetic protein-protein interactions Peptide 01 natural sciences Epitope constrained peptide Epitopes chemistry.chemical_compound Protein structure Transcription (biology) Research Articles chemistry.chemical_classification peptide inhibitor 0303 health sciences Chemistry General Medicine Cell biology protein–DNA interactions Cross-Linking Reagents medicine.anatomical_structure Thermodynamics Crystallization Research Article Protein Binding Macrocyclic Compounds Flexibility (anatomy) protein-DNA interaction protein–protein interactions Molecular Dynamics Simulation 010402 general chemistry Methylation Catalysis Protein–protein interaction 03 medical and health sciences medicine Humans protein structure Transcription factor 030304 developmental biology Binding Sites Base Sequence 010405 organic chemistry DNA General Chemistry constrained peptides peptide inhibitors 0104 chemical sciences CCAAT-Binding Factor Biophysics Peptidomimetics Protein Multimerization Peptides |
| Zdroj: | Angewandte Chemie (International Ed. in English) Jeganathan, S, Wendt, M, Kiehstaller, S, Brancaccio, D, Kuepper, A, Pospiech, N, Carotenuto, A, Novellino, E, Hennig, S & Grossmann, T N 2019, ' Constrained Peptides with Fine-Tuned Flexibility Inhibit NF-Y Transcription Factor Assembly ', Angewandte Chemie. International Edition, vol. 58, no. 48, pp. 17351-17358 . https://doi.org/10.1002/anie.201907901 Angewandte Chemie |
| ISSN: | 1521-3757 0044-8249 |
| DOI: | 10.1002/ange.201907901 |
| Popis: | 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. Set Me free: A peptide‐derived inhibitor of the NF‐Y transcription factor was developed by constraining the conformation of an epitope through hydrocarbon stapling and then fine‐tuning its flexibility. In the initial set of constrained peptides, a non‐interacting α‐methyl group was observed to have a detrimental effect on complex stability. Adaption of the methylation pattern gave a peptide that inhibits transcription factor assembly and subsequent DNA binding. |
| Databáze: | OpenAIRE |
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