GE23077 binds to the RNA polymerase ‘i’ and ‘i+1’ sites and prevents the binding of initiating nucleotides
Using a combination of genetic, biochemical, and structural approaches, we show that the cyclic-peptide antibiotic GE23077 (GE) binds directly to the bacterial RNA polymerase (RNAP) active-center ‘i’ and ‘i+1’ nucleotide binding sites, preventing the binding of initiating nucleotides, and thereby pr...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2014-04-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/02450 |
| _version_ | 1818018966801481728 |
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| author | Yu Zhang David Degen Mary X Ho Elena Sineva Katherine Y Ebright Yon W Ebright Vladimir Mekler Hanif Vahedian-Movahed Yu Feng Ruiheng Yin Steve Tuske Herbert Irschik Rolf Jansen Sonia Maffioli Stefano Donadio Eddy Arnold Richard H Ebright |
| author_facet | Yu Zhang David Degen Mary X Ho Elena Sineva Katherine Y Ebright Yon W Ebright Vladimir Mekler Hanif Vahedian-Movahed Yu Feng Ruiheng Yin Steve Tuske Herbert Irschik Rolf Jansen Sonia Maffioli Stefano Donadio Eddy Arnold Richard H Ebright |
| author_sort | Yu Zhang |
| collection | DOAJ |
| description | Using a combination of genetic, biochemical, and structural approaches, we show that the cyclic-peptide antibiotic GE23077 (GE) binds directly to the bacterial RNA polymerase (RNAP) active-center ‘i’ and ‘i+1’ nucleotide binding sites, preventing the binding of initiating nucleotides, and thereby preventing transcription initiation. The target-based resistance spectrum for GE is unusually small, reflecting the fact that the GE binding site on RNAP includes residues of the RNAP active center that cannot be substituted without loss of RNAP activity. The GE binding site on RNAP is different from the rifamycin binding site. Accordingly, GE and rifamycins do not exhibit cross-resistance, and GE and a rifamycin can bind simultaneously to RNAP. The GE binding site on RNAP is immediately adjacent to the rifamycin binding site. Accordingly, covalent linkage of GE to a rifamycin provides a bipartite inhibitor having very high potency and very low susceptibility to target-based resistance. |
| first_indexed | 2024-04-14T07:45:42Z |
| format | Article |
| id | doaj.art-f4f3d502427d47b09fde0b71d754abf6 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-14T07:45:42Z |
| publishDate | 2014-04-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-f4f3d502427d47b09fde0b71d754abf62022-12-22T02:05:20ZengeLife Sciences Publications LtdeLife2050-084X2014-04-01310.7554/eLife.02450GE23077 binds to the RNA polymerase ‘i’ and ‘i+1’ sites and prevents the binding of initiating nucleotidesYu Zhang0David Degen1Mary X Ho2Elena Sineva3Katherine Y Ebright4Yon W Ebright5Vladimir Mekler6Hanif Vahedian-Movahed7Yu Feng8Ruiheng Yin9Steve Tuske10Herbert Irschik11Rolf Jansen12Sonia Maffioli13Stefano Donadio14Eddy Arnold15Richard H Ebright16Waksman Institute, Rutgers University, Piscataway, United States; Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, United StatesWaksman Institute, Rutgers University, Piscataway, United States; Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, United StatesDepartment of Chemistry and Chemical Biology, Rutgers University, Piscataway, United States; Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, United StatesWaksman Institute, Rutgers University, Piscataway, United States; Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, United StatesWaksman Institute, Rutgers University, Piscataway, United States; Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, United StatesWaksman Institute, Rutgers University, Piscataway, United States; Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, United StatesWaksman Institute, Rutgers University, Piscataway, United States; Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, United StatesWaksman Institute, Rutgers University, Piscataway, United States; Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, United StatesWaksman Institute, Rutgers University, Piscataway, United States; Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, United StatesWaksman Institute, Rutgers University, Piscataway, United States; Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, United StatesDepartment of Chemistry and Chemical Biology, Rutgers University, Piscataway, United States; Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, United StatesNatural Products Chemistry, Helmholtz Centre for Infection Research, Braunschweig, GermanyMicrobial Drugs, Helmholtz Centre for Infection Research, Braunschweig, GermanyNaicons Srl, Milan, ItalyNaicons Srl, Milan, ItalyDepartment of Chemistry and Chemical Biology, Rutgers University, Piscataway, United States; Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, United StatesWaksman Institute, Rutgers University, Piscataway, United States; Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, United StatesUsing a combination of genetic, biochemical, and structural approaches, we show that the cyclic-peptide antibiotic GE23077 (GE) binds directly to the bacterial RNA polymerase (RNAP) active-center ‘i’ and ‘i+1’ nucleotide binding sites, preventing the binding of initiating nucleotides, and thereby preventing transcription initiation. The target-based resistance spectrum for GE is unusually small, reflecting the fact that the GE binding site on RNAP includes residues of the RNAP active center that cannot be substituted without loss of RNAP activity. The GE binding site on RNAP is different from the rifamycin binding site. Accordingly, GE and rifamycins do not exhibit cross-resistance, and GE and a rifamycin can bind simultaneously to RNAP. The GE binding site on RNAP is immediately adjacent to the rifamycin binding site. Accordingly, covalent linkage of GE to a rifamycin provides a bipartite inhibitor having very high potency and very low susceptibility to target-based resistance.https://elifesciences.org/articles/02450RNA polymeraseRNA polymerase-promoter open complextranscriptiontranscription initiationinhibitorbipartite inhibitor |
| spellingShingle | Yu Zhang David Degen Mary X Ho Elena Sineva Katherine Y Ebright Yon W Ebright Vladimir Mekler Hanif Vahedian-Movahed Yu Feng Ruiheng Yin Steve Tuske Herbert Irschik Rolf Jansen Sonia Maffioli Stefano Donadio Eddy Arnold Richard H Ebright GE23077 binds to the RNA polymerase ‘i’ and ‘i+1’ sites and prevents the binding of initiating nucleotides eLife RNA polymerase RNA polymerase-promoter open complex transcription transcription initiation inhibitor bipartite inhibitor |
| title | GE23077 binds to the RNA polymerase ‘i’ and ‘i+1’ sites and prevents the binding of initiating nucleotides |
| title_full | GE23077 binds to the RNA polymerase ‘i’ and ‘i+1’ sites and prevents the binding of initiating nucleotides |
| title_fullStr | GE23077 binds to the RNA polymerase ‘i’ and ‘i+1’ sites and prevents the binding of initiating nucleotides |
| title_full_unstemmed | GE23077 binds to the RNA polymerase ‘i’ and ‘i+1’ sites and prevents the binding of initiating nucleotides |
| title_short | GE23077 binds to the RNA polymerase ‘i’ and ‘i+1’ sites and prevents the binding of initiating nucleotides |
| title_sort | ge23077 binds to the rna polymerase i and i 1 sites and prevents the binding of initiating nucleotides |
| topic | RNA polymerase RNA polymerase-promoter open complex transcription transcription initiation inhibitor bipartite inhibitor |
| url | https://elifesciences.org/articles/02450 |
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