Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/105502
Title: Structural insights reveal a recognition feature for tailoring hydrocarbon stapled-peptides against the eukaryotic translation initiation factor 4E protein
Authors: Lama, Dilraj
Liberatore, Anne-Marie
Frosi, Yuri
Nakhle, Jessica
Tsomaia, Natia
Bashir, Tarig
Lane, David P.
Brown, Christopher J.
Verma, Chandra Shekhar
Auvin, Serge
Keywords: DRNTU::Science::Biological sciences
Eukaryotic Translation
4E Protein
Issue Date: 2019
Source: Lama, D., Liberatore, A.-M., Frosi, Y., Nakhle, J., Tsomaia, N., Bashir, T., . . . Auvin, S. (2019). Structural insights reveal a recognition feature for tailoring hydrocarbon stapled-peptides against the eukaryotic translation initiation factor 4E protein. Chemical Science, 10(8), 2489-2500. doi:10.1039/C8SC03759K
Series/Report no.: Chemical Science
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.
URI: https://hdl.handle.net/10356/105502
http://hdl.handle.net/10220/47812
ISSN: 2041-6520
DOI: 10.1039/C8SC03759K
Rights: © 2019 The Author(s) (published by Royal Society of Chemistry). This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence.
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:SPMS Journal Articles

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