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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...

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Autores principales: Yakimov, Alexander, Pobegalov, Georgii, Bakhlanova, Irina, Khodorkovskii, Mikhail, Petukhov, Michael, Baitin, Dmitry
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2017
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.
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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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