5ZML

Stapled-peptides tailored against initiation of translation

Summary for 5ZML

• Entry DOI: 10.2210/pdb5zml/pdb
• Descriptor: Eukaryotic translation initiation factor 4E, ACE-LYS-LYS-ARG-TYR-SER-ARG-MK8-GLN-LEU-LEU-MK8-PHE-ARG-ARG, NITRATE ION, ... (5 entities in total)
• Functional Keywords: cap dependent translation, rna binding protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 24631.08

Authors

Lama, D.,Liberator, A.,Frosi, Y.,Nakhle, J.,Tsomia, N.,Bashir, T.,Lane, D.P.,Brown, C.J.,Verma, C.S.,Auvin, S.,Yano, J. (deposition date: 2018-04-04, release date: 2019-02-20, Last modification date: 2024-10-23)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.8 Å)