GE23077 binds to the RNA polymerase 'i' and 'i+1' sites and prevents the binding of initiating nucleotides.
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Authors
Zhang, YuDegen, 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
Issue Date
2014
Metadata
Show full item recordAbstract
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.Citation
GE23077 binds to the RNA polymerase 'i' and 'i+1' sites and prevents the binding of initiating nucleotides. 2014, 3:e02450 ElifeAffiliation
Dept. Micribial Derugs, Helmholtz Centre for infection research, Inhoffenstr. 7, D-38124 Braunschweig, Germany.Journal
eLifePubMed ID
24755292Type
ArticleLanguage
enISSN
2050-084XThe following license files are associated with this item:
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