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Transcription inhibition by the depsipeptide antibiotic salinamide A
We report that bacterial RNA polymerase (RNAP) is the functional cellular target of the depsipeptide antibiotic salinamide A (Sal), and we report that Sal inhibits RNAP through a novel binding site and mechanism. We show that Sal inhibits RNA synthesis in cells and that mutations that confer Sal-res...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4029172/ https://www.ncbi.nlm.nih.gov/pubmed/24843001 http://dx.doi.org/10.7554/eLife.02451 |
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author | Degen, David Feng, Yu Zhang, Yu Ebright, Katherine Y Ebright, Yon W Gigliotti, Matthew Vahedian-Movahed, Hanif Mandal, Sukhendu Talaue, Meliza Connell, Nancy Arnold, Eddy Fenical, William Ebright, Richard H |
author_facet | Degen, David Feng, Yu Zhang, Yu Ebright, Katherine Y Ebright, Yon W Gigliotti, Matthew Vahedian-Movahed, Hanif Mandal, Sukhendu Talaue, Meliza Connell, Nancy Arnold, Eddy Fenical, William Ebright, Richard H |
author_sort | Degen, David |
collection | PubMed |
description | We report that bacterial RNA polymerase (RNAP) is the functional cellular target of the depsipeptide antibiotic salinamide A (Sal), and we report that Sal inhibits RNAP through a novel binding site and mechanism. We show that Sal inhibits RNA synthesis in cells and that mutations that confer Sal-resistance map to RNAP genes. We show that Sal interacts with the RNAP active-center ‘bridge-helix cap’ comprising the ‘bridge-helix N-terminal hinge’, ‘F-loop’, and ‘link region’. We show that Sal inhibits nucleotide addition in transcription initiation and elongation. We present a crystal structure that defines interactions between Sal and RNAP and effects of Sal on RNAP conformation. We propose that Sal functions by binding to the RNAP bridge-helix cap and preventing conformational changes of the bridge-helix N-terminal hinge necessary for nucleotide addition. The results provide a target for antibacterial drug discovery and a reagent to probe conformation and function of the bridge-helix N-terminal hinge. DOI: http://dx.doi.org/10.7554/eLife.02451.001 |
format | Online Article Text |
id | pubmed-4029172 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-40291722014-05-22 Transcription inhibition by the depsipeptide antibiotic salinamide A Degen, David Feng, Yu Zhang, Yu Ebright, Katherine Y Ebright, Yon W Gigliotti, Matthew Vahedian-Movahed, Hanif Mandal, Sukhendu Talaue, Meliza Connell, Nancy Arnold, Eddy Fenical, William Ebright, Richard H eLife Biochemistry We report that bacterial RNA polymerase (RNAP) is the functional cellular target of the depsipeptide antibiotic salinamide A (Sal), and we report that Sal inhibits RNAP through a novel binding site and mechanism. We show that Sal inhibits RNA synthesis in cells and that mutations that confer Sal-resistance map to RNAP genes. We show that Sal interacts with the RNAP active-center ‘bridge-helix cap’ comprising the ‘bridge-helix N-terminal hinge’, ‘F-loop’, and ‘link region’. We show that Sal inhibits nucleotide addition in transcription initiation and elongation. We present a crystal structure that defines interactions between Sal and RNAP and effects of Sal on RNAP conformation. We propose that Sal functions by binding to the RNAP bridge-helix cap and preventing conformational changes of the bridge-helix N-terminal hinge necessary for nucleotide addition. The results provide a target for antibacterial drug discovery and a reagent to probe conformation and function of the bridge-helix N-terminal hinge. DOI: http://dx.doi.org/10.7554/eLife.02451.001 eLife Sciences Publications, Ltd 2014-04-30 /pmc/articles/PMC4029172/ /pubmed/24843001 http://dx.doi.org/10.7554/eLife.02451 Text en Copyright © 2014, Degen et al http://creativecommons.org/licenses/by/3.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Biochemistry Degen, David Feng, Yu Zhang, Yu Ebright, Katherine Y Ebright, Yon W Gigliotti, Matthew Vahedian-Movahed, Hanif Mandal, Sukhendu Talaue, Meliza Connell, Nancy Arnold, Eddy Fenical, William Ebright, Richard H Transcription inhibition by the depsipeptide antibiotic salinamide A |
title | Transcription inhibition by the depsipeptide antibiotic salinamide A |
title_full | Transcription inhibition by the depsipeptide antibiotic salinamide A |
title_fullStr | Transcription inhibition by the depsipeptide antibiotic salinamide A |
title_full_unstemmed | Transcription inhibition by the depsipeptide antibiotic salinamide A |
title_short | Transcription inhibition by the depsipeptide antibiotic salinamide A |
title_sort | transcription inhibition by the depsipeptide antibiotic salinamide a |
topic | Biochemistry |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4029172/ https://www.ncbi.nlm.nih.gov/pubmed/24843001 http://dx.doi.org/10.7554/eLife.02451 |
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