4BEA: Crystal Structure of Eif4e in Complex With a Stapled Peptide Derivative

eIF4E is frequently over-expressed in different cancers and causes increased translation of oncogenic proteins via deregulated cap-dependent translation. Inhibitors of the eIF4E:eIF4G interactions represent an approach that would normalize cap-dependent translation. Stapled peptides represent an emerging class of therapeutics that can target protein: protein interactions. We present here molecular dynamics simulations for a set of rationally designed stapled peptides in solution and in complex with eIF4E, supported with biophysical and crystallographic data. Clustering of the simulated structures revealed the favoured conformational states of the stapled peptides in their bound or free forms in solution. Identifying these populations has allowed us to design peptides with improved affinities by introducing mutations into the peptide sequence to alter their conformational distributions. These studies emphasise the effects that engineered mutations have on the conformations of free and bound peptides, and illustrate that both states must be considered in efforts to attain high affinity binding.
PDB ID: 4BEADownload
MMDB ID: 115761
PDB Deposition Date: 2013/3/7
Updated in MMDB: 2013/12
Experimental Method:
x-ray diffraction
Resolution: 2.57  Å
Source Organism:
synthetic construct
Similar Structures:
Biological Unit for 4BEA: dimeric; determined by author and by software (PISA)
Molecular Components in 4BEA
Label Count Molecule
Proteins (2 molecules)
Eukaryotic Translation Initiation Factor 4E(Gene symbol: EIF4E)
Molecule annotation
Stapled Eif4e Interacting Peptide
Molecule annotation
* Click molecule labels to explore molecular sequence information.

Citing MMDB