Improved eIF4E binding peptides by phage display guided design: plasticity of interacting surfaces yield collective effects.

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 regard...

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Autores principales:	Weizhuang Zhou, Soo T Quah, Chandra S Verma, Yun Liu, David P Lane, Christopher J Brown
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/55da2c89814e4f45acde4561acea2d16
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spelling	oai:doaj.org-article:55da2c89814e4f45acde4561acea2d162021-11-18T08:11:30ZImproved eIF4E binding peptides by phage display guided design: plasticity of interacting surfaces yield collective effects.1932-620310.1371/journal.pone.0047235https://doaj.org/article/55da2c89814e4f45acde4561acea2d162012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23094039/?tool=EBIhttps://doaj.org/toc/1932-6203Eukaryotic 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.Weizhuang ZhouSoo T QuahChandra S VermaYun LiuDavid P LaneChristopher J BrownPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 10, p e47235 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Weizhuang Zhou Soo T Quah Chandra S Verma Yun Liu David P Lane Christopher J Brown Improved eIF4E binding peptides by phage display guided design: plasticity of interacting surfaces yield collective effects.
description	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.
format	article
author	Weizhuang Zhou Soo T Quah Chandra S Verma Yun Liu David P Lane Christopher J Brown
author_facet	Weizhuang Zhou Soo T Quah Chandra S Verma Yun Liu David P Lane Christopher J Brown
author_sort	Weizhuang Zhou
title	Improved eIF4E binding peptides by phage display guided design: plasticity of interacting surfaces yield collective effects.
title_short	Improved eIF4E binding peptides by phage display guided design: plasticity of interacting surfaces yield collective effects.
title_full	Improved eIF4E binding peptides by phage display guided design: plasticity of interacting surfaces yield collective effects.
title_fullStr	Improved eIF4E binding peptides by phage display guided design: plasticity of interacting surfaces yield collective effects.
title_full_unstemmed	Improved eIF4E binding peptides by phage display guided design: plasticity of interacting surfaces yield collective effects.
title_sort	improved eif4e binding peptides by phage display guided design: plasticity of interacting surfaces yield collective effects.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/55da2c89814e4f45acde4561acea2d16
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Improved eIF4E binding peptides by phage display guided design: plasticity of interacting surfaces yield collective effects.

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