4AZA

Improved eIF4E binding peptides by phage display guided design.

Summary for 4AZA

• Entry DOI: 10.2210/pdb4aza/pdb
• Related: 1IPB 1IPC 2V8W 2V8X 2V8Y 2W97
• Descriptor: EUKARYOTIC TRANSLATION INITIATION FACTOR 4E, EIF4G1_D5S PEPTIDE, [[(2R,3S,4R,5R)-5-(6-AMINO-3-METHYL-4-OXO-5H-IMIDAZO[4,5-C]PYRIDIN-1-YL)-3,4-DIHYDROXY-OXOLAN-2-YL]METHOXY-HYDROXY-PHOSPHORYL] PHOSPHONO HYDROGEN PHOSPHATE, ... (4 entities in total)
• Functional Keywords: translation
• Biological source: HOMO SAPIENS (HUMAN); More
• Cellular location: Cytoplasm, P-body: P06730
• Total number of polymer chains: 4
• Total formula weight: 54478.71

Authors

Chew, W.Z.,Quah, S.T.,Verma, C.S.,Liu, Y.,Lane, D.P.,Brown, C.J. (deposition date: 2012-06-25, release date: 2012-08-08, Last modification date: 2024-11-20)

Primary citation

Zhou, W.,Quah, S.T.,Verma, C.S.,Liu, Y.,Lane, D.P.,Brown, C.J.
Improved Eif4E Binding Peptides by Phage Display Guided Design: Plasticity of Interacting Surfaces Yield Collective Effects.
Plos One, 7:47235-, 2012

PubMed Abstract: Eukaryotic initiation factor (eIF)4E is over-expressed in many types of cancer such as breast, head and neck, and lung. A consequence of increased levels of eIF4E is the preferential translation of pro-tumorigenic proteins (e.g. c-Myc and vascular endothelial growth factor) and as a result is regarded as a potential therapeutic target. In this work a novel phage display peptide has been isolated against eIF4E. From the phage sequence two amino acids were delineated which improved binding when substituted into the eIF4G1 sequence. Neither of these substitutions were involved in direct interactions with eIF4E and acted either via optimization of the helical capping motif or restricting the conformational flexibility of the peptide. In contrast, substitutions of the remaining phage derived amino acids into the eIF4G1 sequence disrupted binding of the peptide to eIF4E. Interestingly when some of these disruptive substitutions were combined with key mutations from the phage peptide, they lead to improved affinities. Atomistic computer simulations revealed that the phage and the eIF4G1 derivative peptide sequences differ subtly in their interaction sites on eIF4E. This raises the issue, especially in the context of planar interaction sites such as those exhibited by eIF4E, that given the intricate plasticity of protein surfaces, the construction of structure-activity relationships should account for the possibility of significant movement in the spatial positioning of the peptide binding interface, including significant librational motions of the peptide.

PubMed: 23094039
DOI: 10.1371/JOURNAL.PONE.0047235

Experimental method

X-RAY DIFFRACTION (2.16 Å)