Abstract
AbstractProtein 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.
Highlights
The assembly of proteins into multimeric complexes is central to many biological processes
In the initial set of constrained peptides, a single non-interacting a-methyl group was observed to have a detrimental effect on complex stability
Aiming for the structural characterization of PBM bound to NF-YB/C (B: aa 51-143; C: aa 27-120) in the absence of DNA, crystallization conditions were screened to provide crystals diffracting to 2.0
Summary
The assembly of proteins into multimeric complexes is central to many biological processes. The underlying protein– protein interactions (PPIs) involve a multitude of individual amino acid contacts and require the involved proteins to adopt a defined, but partially flexible, three-dimensional [+] These authors contributed to this work.
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