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Blocking the RecA activity and SOS-response in bacteria with a short α-helical peptide
The RecX protein, a very active natural RecA protein inhibitor, can completely disassemble RecA filaments at nanomolar concentrations that are two to three orders of magnitude lower than that of RecA protein. Based on the structure of RecX protein complex with the presynaptic RecA filament, we desig...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5766188/ https://www.ncbi.nlm.nih.gov/pubmed/28934502 http://dx.doi.org/10.1093/nar/gkx687 |
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author | Yakimov, Alexander Pobegalov, Georgii Bakhlanova, Irina Khodorkovskii, Mikhail Petukhov, Michael Baitin, Dmitry |
author_facet | Yakimov, Alexander Pobegalov, Georgii Bakhlanova, Irina Khodorkovskii, Mikhail Petukhov, Michael Baitin, Dmitry |
author_sort | Yakimov, Alexander |
collection | PubMed |
description | The RecX protein, a very active natural RecA protein inhibitor, can completely disassemble RecA filaments at nanomolar concentrations that are two to three orders of magnitude lower than that of RecA protein. Based on the structure of RecX protein complex with the presynaptic RecA filament, we designed a short first in class α-helical peptide that both inhibits RecA protein activities in vitro and blocks the bacterial SOS-response in vivo. The peptide was designed using SEQOPT, a novel method for global sequence optimization of protein α-helices. SEQOPT produces artificial peptide sequences containing only 20 natural amino acids with the maximum possible conformational stability at a given pH, ionic strength, temperature, peptide solubility. It also accounts for restrictions due to known amino acid residues involved in stabilization of protein complexes under consideration. The results indicate that a few key intermolecular interactions inside the RecA protein presynaptic complex are enough to reproduce the main features of the RecX protein mechanism of action. Since the SOS-response provides a major mechanism of bacterial adaptation to antibiotics, these results open new ways for the development of antibiotic co-therapy that would not cause bacterial resistance. |
format | Online Article Text |
id | pubmed-5766188 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-57661882018-01-19 Blocking the RecA activity and SOS-response in bacteria with a short α-helical peptide Yakimov, Alexander Pobegalov, Georgii Bakhlanova, Irina Khodorkovskii, Mikhail Petukhov, Michael Baitin, Dmitry Nucleic Acids Res Synthetic Biology and Bioengineering The RecX protein, a very active natural RecA protein inhibitor, can completely disassemble RecA filaments at nanomolar concentrations that are two to three orders of magnitude lower than that of RecA protein. Based on the structure of RecX protein complex with the presynaptic RecA filament, we designed a short first in class α-helical peptide that both inhibits RecA protein activities in vitro and blocks the bacterial SOS-response in vivo. The peptide was designed using SEQOPT, a novel method for global sequence optimization of protein α-helices. SEQOPT produces artificial peptide sequences containing only 20 natural amino acids with the maximum possible conformational stability at a given pH, ionic strength, temperature, peptide solubility. It also accounts for restrictions due to known amino acid residues involved in stabilization of protein complexes under consideration. The results indicate that a few key intermolecular interactions inside the RecA protein presynaptic complex are enough to reproduce the main features of the RecX protein mechanism of action. Since the SOS-response provides a major mechanism of bacterial adaptation to antibiotics, these results open new ways for the development of antibiotic co-therapy that would not cause bacterial resistance. Oxford University Press 2017-09-19 2017-08-02 /pmc/articles/PMC5766188/ /pubmed/28934502 http://dx.doi.org/10.1093/nar/gkx687 Text en © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Synthetic Biology and Bioengineering Yakimov, Alexander Pobegalov, Georgii Bakhlanova, Irina Khodorkovskii, Mikhail Petukhov, Michael Baitin, Dmitry Blocking the RecA activity and SOS-response in bacteria with a short α-helical peptide |
title | Blocking the RecA activity and SOS-response in bacteria with a short α-helical peptide |
title_full | Blocking the RecA activity and SOS-response in bacteria with a short α-helical peptide |
title_fullStr | Blocking the RecA activity and SOS-response in bacteria with a short α-helical peptide |
title_full_unstemmed | Blocking the RecA activity and SOS-response in bacteria with a short α-helical peptide |
title_short | Blocking the RecA activity and SOS-response in bacteria with a short α-helical peptide |
title_sort | blocking the reca activity and sos-response in bacteria with a short α-helical peptide |
topic | Synthetic Biology and Bioengineering |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5766188/ https://www.ncbi.nlm.nih.gov/pubmed/28934502 http://dx.doi.org/10.1093/nar/gkx687 |
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