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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Main Authors: Zhou, Weizhuang., Verma, Chandra Shekhar., Liu, Yun., Lane, David P., Brown, Christopher J., Tng, Quah Soo.
Other Authors: School of Biological Sciences
Format: Article
Language:English
Published: 2013
Online Access:https://hdl.handle.net/10356/95361
http://hdl.handle.net/10220/9217
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Institution: Nanyang Technological University
Language: English
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spelling sg-ntu-dr.10356-953612023-02-28T17:01:58Z Improved eIF4E binding peptides by phage display guided design : plasticity of interacting surfaces yield collective effects Zhou, Weizhuang. Verma, Chandra Shekhar. Liu, Yun. Lane, David P. Brown, Christopher J. Tng, Quah Soo. School of Biological Sciences 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. Published version 2013-02-21T07:22:27Z 2019-12-06T19:13:26Z 2013-02-21T07:22:27Z 2019-12-06T19:13:26Z 2012 2012 Journal Article Zhou, W., Tng, Q. S., Verma, C. S., Liu, Y., Lane, D. P., & Brown, C. J. (2012). Improved eIF4E binding peptides by phage display guided design : plasticity of interacting surfaces yield collective effects. PLoS ONE, 7(10). 1932-6203 https://hdl.handle.net/10356/95361 http://hdl.handle.net/10220/9217 10.1371/journal.pone.0047235 23094039 en PLoS ONE © 2012 The Authors. application/pdf
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
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.
author2 School of Biological Sciences
author_facet School of Biological Sciences
Zhou, Weizhuang.
Verma, Chandra Shekhar.
Liu, Yun.
Lane, David P.
Brown, Christopher J.
Tng, Quah Soo.
format Article
author Zhou, Weizhuang.
Verma, Chandra Shekhar.
Liu, Yun.
Lane, David P.
Brown, Christopher J.
Tng, Quah Soo.
spellingShingle Zhou, Weizhuang.
Verma, Chandra Shekhar.
Liu, Yun.
Lane, David P.
Brown, Christopher J.
Tng, Quah Soo.
Improved eIF4E binding peptides by phage display guided design : plasticity of interacting surfaces yield collective effects
author_sort Zhou, Weizhuang.
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
publishDate 2013
url https://hdl.handle.net/10356/95361
http://hdl.handle.net/10220/9217
_version_ 1759854434864594944