Structural insights reveal a recognition feature for tailoring hydrocarbon stapled-peptides against the eukaryotic translation initiation factor 4E protein
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 tran...
| Main Authors: | , , , , , , , , , |
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| Format: | Journal Article |
| Language: | English |
| Published: |
2019
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| Online Access: | https://hdl.handle.net/10356/105502 http://hdl.handle.net/10220/47812 |
| _version_ | 1826116870784155648 |
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| author | Lama, Dilraj Liberatore, Anne-Marie Frosi, Yuri Nakhle, Jessica Tsomaia, Natia Bashir, Tarig Lane, David P. Brown, Christopher J. Verma, Chandra Shekhar Auvin, Serge |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences Lama, Dilraj Liberatore, Anne-Marie Frosi, Yuri Nakhle, Jessica Tsomaia, Natia Bashir, Tarig Lane, David P. Brown, Christopher J. Verma, Chandra Shekhar Auvin, Serge |
| author_sort | Lama, Dilraj |
| collection | NTU |
| description | 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. |
| first_indexed | 2024-10-01T04:18:30Z |
| format | Journal Article |
| id | ntu-10356/105502 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T04:18:30Z |
| publishDate | 2019 |
| record_format | dspace |
| spelling | ntu-10356/1055022023-02-28T19:43:25Z Structural insights reveal a recognition feature for tailoring hydrocarbon stapled-peptides against the eukaryotic translation initiation factor 4E protein Lama, Dilraj Liberatore, Anne-Marie Frosi, Yuri Nakhle, Jessica Tsomaia, Natia Bashir, Tarig Lane, David P. Brown, Christopher J. Verma, Chandra Shekhar Auvin, Serge School of Biological Sciences DRNTU::Science::Biological sciences Eukaryotic Translation 4E Protein 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. ASTAR (Agency for Sci., Tech. and Research, S’pore) Published version 2019-03-14T06:39:09Z 2019-12-06T21:52:37Z 2019-03-14T06:39:09Z 2019-12-06T21:52:37Z 2019 Journal Article 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 2041-6520 https://hdl.handle.net/10356/105502 http://hdl.handle.net/10220/47812 10.1039/C8SC03759K en Chemical Science © 2019 The Author(s) (published by Royal Society of Chemistry). This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. 12 p. application/pdf |
| spellingShingle | DRNTU::Science::Biological sciences Eukaryotic Translation 4E Protein Lama, Dilraj Liberatore, Anne-Marie Frosi, Yuri Nakhle, Jessica Tsomaia, Natia Bashir, Tarig Lane, David P. Brown, Christopher J. Verma, Chandra Shekhar Auvin, Serge Structural insights reveal a recognition feature for tailoring hydrocarbon stapled-peptides against the eukaryotic translation initiation factor 4E protein |
| title | Structural insights reveal a recognition feature for tailoring hydrocarbon stapled-peptides against the eukaryotic translation initiation factor 4E protein |
| title_full | Structural insights reveal a recognition feature for tailoring hydrocarbon stapled-peptides against the eukaryotic translation initiation factor 4E protein |
| title_fullStr | Structural insights reveal a recognition feature for tailoring hydrocarbon stapled-peptides against the eukaryotic translation initiation factor 4E protein |
| title_full_unstemmed | Structural insights reveal a recognition feature for tailoring hydrocarbon stapled-peptides against the eukaryotic translation initiation factor 4E protein |
| title_short | Structural insights reveal a recognition feature for tailoring hydrocarbon stapled-peptides against the eukaryotic translation initiation factor 4E protein |
| title_sort | structural insights reveal a recognition feature for tailoring hydrocarbon stapled peptides against the eukaryotic translation initiation factor 4e protein |
| topic | DRNTU::Science::Biological sciences Eukaryotic Translation 4E Protein |
| url | https://hdl.handle.net/10356/105502 http://hdl.handle.net/10220/47812 |
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