Conformational ordering of intrinsically disordered peptides for targeting translation initiation.
Conformational selection
Disorder-to-order transition
Intrinsically disordered regions
Peptide-based inhibitors
Protein-protein interactions
Journal
Biochimica et biophysica acta. General subjects
ISSN: 1872-8006
Titre abrégé: Biochim Biophys Acta Gen Subj
Pays: Netherlands
ID NLM: 101731726
Informations de publication
Date de publication:
01 2021
01 2021
Historique:
received:
21
08
2020
revised:
14
10
2020
accepted:
22
10
2020
pubmed:
31
10
2020
medline:
12
1
2021
entrez:
30
10
2020
Statut:
ppublish
Résumé
Intrinsically disordered regions (IDRs) in proteins can regulate their activity by facilitating protein-protein interactions (PPIs) as exemplified in the recruitment of the eukaryotic translation initiation factor 4E (eIF4E) protein by the protein eIF4G. Deregulation of this PPI module is central to a broad spectrum of cancer related malignancies and its targeted inhibition through bioactive peptides is a promising strategy for therapeutic intervention. We employed molecular dynamics simulations coupled with biophysical assays to rationally develop peptide derivatives from the intrinsically disordered eIF4G scaffold by incorporating non-natural amino acids that facilitates disorder-to-order transition. The conformational heterogeneity of these peptides and the degree of structural reorganization required to adopt the optimum mode of interaction with eIF4E underscores their differential binding affinities. The presence of a pre-structured local helical element in the ensemble of structures was instrumental in the efficient docking of the peptides on to the protein surface. The formation of Y4: P38 hydrogen-bond interaction between the peptide and eIF4E is a rate limiting event in the efficient recognition of the protein since it occurs through the disordered region of the peptide. These insights were exploited to further design features into the peptide to propagate bound-state conformations in solution which resulted in the generation of a potent eIF4E binder. The study illustrates the molecular basis of eIF4E recognition by a disordered epitope from eIF4G and its modulation to generate peptides that can potentially attenuate translation initiation in oncology.
Sections du résumé
BACKGROUND
Intrinsically disordered regions (IDRs) in proteins can regulate their activity by facilitating protein-protein interactions (PPIs) as exemplified in the recruitment of the eukaryotic translation initiation factor 4E (eIF4E) protein by the protein eIF4G. Deregulation of this PPI module is central to a broad spectrum of cancer related malignancies and its targeted inhibition through bioactive peptides is a promising strategy for therapeutic intervention.
METHODS
We employed molecular dynamics simulations coupled with biophysical assays to rationally develop peptide derivatives from the intrinsically disordered eIF4G scaffold by incorporating non-natural amino acids that facilitates disorder-to-order transition.
RESULTS
The conformational heterogeneity of these peptides and the degree of structural reorganization required to adopt the optimum mode of interaction with eIF4E underscores their differential binding affinities. The presence of a pre-structured local helical element in the ensemble of structures was instrumental in the efficient docking of the peptides on to the protein surface. The formation of Y4: P38 hydrogen-bond interaction between the peptide and eIF4E is a rate limiting event in the efficient recognition of the protein since it occurs through the disordered region of the peptide.
CONCLUSIONS
These insights were exploited to further design features into the peptide to propagate bound-state conformations in solution which resulted in the generation of a potent eIF4E binder.
GENERAL SIGNIFICANCE
The study illustrates the molecular basis of eIF4E recognition by a disordered epitope from eIF4G and its modulation to generate peptides that can potentially attenuate translation initiation in oncology.
Identifiants
pubmed: 33122085
pii: S0304-4165(20)30286-5
doi: 10.1016/j.bbagen.2020.129775
pii:
doi:
Substances chimiques
Eukaryotic Initiation Factor-4E
0
Eukaryotic Initiation Factor-4G
0
Intrinsically Disordered Proteins
0
Peptides
0
Recombinant Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
129775Informations de copyright
Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.