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Backbone distortions in lactam‐bridged helical peptides
Side‐chain‐to‐side‐chain cyclization is frequently used to stabilize the α‐helical conformation of short peptides. In a previous study, we incorporated a lactam bridge between the side chains of Lys‐i and Asp‐i+4 in the nonapeptide 1Y, cyclo‐(2,6)‐(Ac‐VKRLQDLQY‐NH ( 2 )), an artificial ligand of the...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9285742/ https://www.ncbi.nlm.nih.gov/pubmed/34984761 http://dx.doi.org/10.1002/psc.3400 |
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author | Moazzam, Ali Stanojlovic, Vesna Hinterholzer, Arthur Holzner, Christoph Roschger, Cornelia Zierer, Andreas Wiederstein, Markus Schubert, Mario Cabrele, Chiara |
author_facet | Moazzam, Ali Stanojlovic, Vesna Hinterholzer, Arthur Holzner, Christoph Roschger, Cornelia Zierer, Andreas Wiederstein, Markus Schubert, Mario Cabrele, Chiara |
author_sort | Moazzam, Ali |
collection | PubMed |
description | Side‐chain‐to‐side‐chain cyclization is frequently used to stabilize the α‐helical conformation of short peptides. In a previous study, we incorporated a lactam bridge between the side chains of Lys‐i and Asp‐i+4 in the nonapeptide 1Y, cyclo‐(2,6)‐(Ac‐VKRLQDLQY‐NH ( 2 )), an artificial ligand of the inhibitor of DNA binding and cell differentiation (ID) protein with antiproliferative activity on cancer cells. Herein, we show that only the cyclized five‐residue segment adopts a helical turn whereas the C‐terminal residues remain flexible. Moreover, we present nine 1Y analogs arising from different combinations of hydrophobic residues (leucine, isoleucine, norleucine, valine, and tyrosine) at positions 1, 4, 7, and 9. All cyclopeptides except one build a lactam‐bridged helical turn; however, residue‐4 reveals less helix character than the neighboring Arg‐3 and Gln‐5, especially with residue‐4 being isoleucine, valine, and tyrosine. Surprisingly, only two cyclopeptides exhibit helix propagation until the C‐terminus, whereas the others share a remarkable outward tilting of the backbone carbonyl of the lactam‐bridged Asp‐6 (>40° deviation from the orientation parallel to the helix axis), which prevents the formation of the H‐bond between Arg‐3 CO and residue‐7 NH: As a result, the propagation of the helix beyond the lactam‐bridged sequence becomes unfavorable. We conclude that, depending on the amino‐acid sequence, the lactam bridge between Lys‐i and Asp‐i+4 can stabilize a helical turn but deviations from the ideal helix geometry are possible: Indeed, besides the outward tilting of the backbone carbonyls, the residues per turn increased from 3.6 (typical of a regular α‐helix) to 4.2, suggesting a partial helix unwinding. |
format | Online Article Text |
id | pubmed-9285742 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-92857422022-07-18 Backbone distortions in lactam‐bridged helical peptides Moazzam, Ali Stanojlovic, Vesna Hinterholzer, Arthur Holzner, Christoph Roschger, Cornelia Zierer, Andreas Wiederstein, Markus Schubert, Mario Cabrele, Chiara J Pept Sci Research Articles Side‐chain‐to‐side‐chain cyclization is frequently used to stabilize the α‐helical conformation of short peptides. In a previous study, we incorporated a lactam bridge between the side chains of Lys‐i and Asp‐i+4 in the nonapeptide 1Y, cyclo‐(2,6)‐(Ac‐VKRLQDLQY‐NH ( 2 )), an artificial ligand of the inhibitor of DNA binding and cell differentiation (ID) protein with antiproliferative activity on cancer cells. Herein, we show that only the cyclized five‐residue segment adopts a helical turn whereas the C‐terminal residues remain flexible. Moreover, we present nine 1Y analogs arising from different combinations of hydrophobic residues (leucine, isoleucine, norleucine, valine, and tyrosine) at positions 1, 4, 7, and 9. All cyclopeptides except one build a lactam‐bridged helical turn; however, residue‐4 reveals less helix character than the neighboring Arg‐3 and Gln‐5, especially with residue‐4 being isoleucine, valine, and tyrosine. Surprisingly, only two cyclopeptides exhibit helix propagation until the C‐terminus, whereas the others share a remarkable outward tilting of the backbone carbonyl of the lactam‐bridged Asp‐6 (>40° deviation from the orientation parallel to the helix axis), which prevents the formation of the H‐bond between Arg‐3 CO and residue‐7 NH: As a result, the propagation of the helix beyond the lactam‐bridged sequence becomes unfavorable. We conclude that, depending on the amino‐acid sequence, the lactam bridge between Lys‐i and Asp‐i+4 can stabilize a helical turn but deviations from the ideal helix geometry are possible: Indeed, besides the outward tilting of the backbone carbonyls, the residues per turn increased from 3.6 (typical of a regular α‐helix) to 4.2, suggesting a partial helix unwinding. John Wiley and Sons Inc. 2022-02-09 2022-07 /pmc/articles/PMC9285742/ /pubmed/34984761 http://dx.doi.org/10.1002/psc.3400 Text en © 2022 The Authors. Journal of Peptide Science published by European Peptide Society and John Wiley & Sons Ltd. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Research Articles Moazzam, Ali Stanojlovic, Vesna Hinterholzer, Arthur Holzner, Christoph Roschger, Cornelia Zierer, Andreas Wiederstein, Markus Schubert, Mario Cabrele, Chiara Backbone distortions in lactam‐bridged helical peptides |
title | Backbone distortions in lactam‐bridged helical peptides |
title_full | Backbone distortions in lactam‐bridged helical peptides |
title_fullStr | Backbone distortions in lactam‐bridged helical peptides |
title_full_unstemmed | Backbone distortions in lactam‐bridged helical peptides |
title_short | Backbone distortions in lactam‐bridged helical peptides |
title_sort | backbone distortions in lactam‐bridged helical peptides |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9285742/ https://www.ncbi.nlm.nih.gov/pubmed/34984761 http://dx.doi.org/10.1002/psc.3400 |
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