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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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 |
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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. |
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School of Biological Sciences |
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School of Biological Sciences Zhou, Weizhuang. Verma, Chandra Shekhar. Liu, Yun. Lane, David P. Brown, Christopher J. Tng, Quah Soo. |
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Article |
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Zhou, Weizhuang. Verma, Chandra Shekhar. Liu, Yun. Lane, David P. Brown, Christopher J. Tng, Quah Soo. |
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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 |
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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 |
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Improved eIF4E binding peptides by phage display guided design : plasticity of interacting surfaces yield collective effects |
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improved eif4e binding peptides by phage display guided design : plasticity of interacting surfaces yield collective effects |
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2013 |
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https://hdl.handle.net/10356/95361 http://hdl.handle.net/10220/9217 |
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