5ZK5

Stapled-peptides tailored against initiation of translation

5ZK5 の概要

• エントリーDOI: 10.2210/pdb5zk5/pdb
• 分子名称: Eukaryotic translation initiation factor 4E, LYS-ARG-TYR-SER-ARG-GLU-GLN-LEU-LEU-MK8-PHE-GLN-ARG-MK8, 7N-METHYL-8-HYDROGUANOSINE-5'-TRIPHOSPHATE, ... (4 entities in total)
• 機能のキーワード: cap dependent translation, rna binding protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 24865.04

構造登録者

Lama, D.,Liberator, A.,Frosi, Y.,Nakhle, J.,Tsomia, N.,Bashir, T.,Lane, D.P.,Brown, C.J.,Verma, C.S.,Auvin, S.,Ciesielski, F.,Uhring, M. (登録日: 2018-03-23, 公開日: 2019-02-20, 最終更新日: 2023-11-22)

主引用文献

Lama, D.,Liberatore, A.M.,Frosi, Y.,Nakhle, J.,Tsomaia, N.,Bashir, T.,Lane, D.P.,Brown, C.J.,Verma, C.S.,Auvin, S.
Structural insights reveal a recognition feature for tailoring hydrocarbon stapled-peptides against the eukaryotic translation initiation factor 4E protein.
Chem Sci, 10:2489-2500, 2019

PubMed Abstract: Stapled-peptides have emerged as an exciting class of molecules which can modulate protein-protein interactions. We have used a structure-guided approach to rationally develop a set of hydrocarbon stapled-peptides with high binding affinities and residence times against the oncogenic eukaryotic translation initiation factor 4E (eIF4E) protein. Crystal structures of these peptides in complex with eIF4E show that they form specific interactions with a region on the protein-binding interface of eIF4E which is distinct from the other well-established canonical interactions. This recognition element is a major molecular determinant underlying the improved binding kinetics of these peptides with eIF4E. The interactions were further exploited by designing features in the peptides to attenuate disorder and increase helicity which collectively resulted in the generation of a distinct class of hydrocarbon stapled-peptides targeting eIF4E. This study details new insights into the molecular basis of stapled-peptide: eIF4E interactions and their exploitation to enhance promising lead molecules for the development of stapled-peptide compounds for oncology.

PubMed: 30881679
DOI: 10.1039/c8sc03759k

実験手法

X-RAY DIFFRACTION (2.25 Å)