GE23077 binds to the RNA polymerase 'i' and 'i+1' sites and prevents the binding of initiating nucleotides.

2.50
Hdl Handle:
http://hdl.handle.net/10033/321647
Title:
GE23077 binds to the RNA polymerase 'i' and 'i+1' sites and prevents the binding of initiating nucleotides.
Authors:
Zhang, Yu; Degen, David; Ho, Mary X; Sineva, Elena; Ebright, Katherine Y; Ebright, Yon W; Mekler, Vladimir; Vahedian-Movahed, Hanif; Feng, Yu; Yin, Ruiheng; Tuske, Steve; Irschik, Herbert; Jansen, Rolf; Maffioli, Sonia; Donadio, Stefano; Arnold, Eddy; Ebright, Richard H
Abstract:
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. DOI: http://dx.doi.org/10.7554/eLife.02450.001.
Affiliation:
Dept. Micribial Derugs, Helmholtz Centre for infection research, Inhoffenstr. 7, D-38124 Braunschweig, Germany.
Citation:
GE23077 binds to the RNA polymerase 'i' and 'i+1' sites and prevents the binding of initiating nucleotides. 2014, 3:e02450 Elife
Journal:
eLife
Issue Date:
2014
URI:
http://hdl.handle.net/10033/321647
PubMed ID:
24755292
Type:
Article
Language:
en
ISSN:
2050-084X
Appears in Collections:
publications of the department of microbial drugs (MWIS)

Full metadata record

DC FieldValue Language
dc.contributor.authorZhang, Yuen
dc.contributor.authorDegen, Daviden
dc.contributor.authorHo, Mary Xen
dc.contributor.authorSineva, Elenaen
dc.contributor.authorEbright, Katherine Yen
dc.contributor.authorEbright, Yon Wen
dc.contributor.authorMekler, Vladimiren
dc.contributor.authorVahedian-Movahed, Hanifen
dc.contributor.authorFeng, Yuen
dc.contributor.authorYin, Ruihengen
dc.contributor.authorTuske, Steveen
dc.contributor.authorIrschik, Herberten
dc.contributor.authorJansen, Rolfen
dc.contributor.authorMaffioli, Soniaen
dc.contributor.authorDonadio, Stefanoen
dc.contributor.authorArnold, Eddyen
dc.contributor.authorEbright, Richard Hen
dc.date.accessioned2014-06-16T12:13:48Z-
dc.date.available2014-06-16T12:13:48Z-
dc.date.issued2014-
dc.identifier.citationGE23077 binds to the RNA polymerase 'i' and 'i+1' sites and prevents the binding of initiating nucleotides. 2014, 3:e02450 Elifeen
dc.identifier.issn2050-084X-
dc.identifier.pmid24755292-
dc.identifier.urihttp://hdl.handle.net/10033/321647-
dc.description.abstractUsing 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. DOI: http://dx.doi.org/10.7554/eLife.02450.001.en
dc.language.isoenen
dc.rightsArchived with thanks to eLifeen
dc.titleGE23077 binds to the RNA polymerase 'i' and 'i+1' sites and prevents the binding of initiating nucleotides.en
dc.typeArticleen
dc.contributor.departmentDept. Micribial Derugs, Helmholtz Centre for infection research, Inhoffenstr. 7, D-38124 Braunschweig, Germany.en
dc.identifier.journaleLifeen

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