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2MBZ

Structural Basis of a Thiopeptide Antibiotic Multidrug Resistance System from Streptomyces lividans:Promothiocin A in Complex with TipAS

Summary for 2MBZ
Entry DOI10.2210/pdb2mbz/pdb
Related1NY9
NMR InformationBMRB: 19421
Related PRD IDPRD_001255
DescriptorHTH-type transcriptional activator TipA, Promothiocin A (2 entities in total)
Functional Keywordstipas/promothiocin a, protein/antibiotic, protein/thiopeptide, multidrug recognition, transcriptional activator, transcription activator-antibiotic complex, transcription activator/antibiotic
Biological sourceStreptomyces lividans
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Total number of polymer chains2
Total formula weight17526.11
Authors
Habazettl, J.,Allan, M.G.,Jensen, P.,Sass, H.,Grzesiek, S. (deposition date: 2013-08-12, release date: 2014-12-10, Last modification date: 2023-11-15)
Primary citationHabazettl, J.,Allan, M.,Jensen, P.R.,Sass, H.J.,Thompson, C.J.,Grzesiek, S.
Structural basis and dynamics of multidrug recognition in a minimal bacterial multidrug resistance system.
Proc. Natl. Acad. Sci. U.S.A., 111:E5498-E5507, 2014
Cited by
PubMed Abstract: TipA is a transcriptional regulator found in diverse bacteria. It constitutes a minimal autoregulated multidrug resistance system against numerous thiopeptide antibiotics. Here we report the structures of its drug-binding domain TipAS in complexes with promothiocin A and nosiheptide, and a model of the thiostrepton complex. Drug binding induces a large transition from a partially unfolded to a globin-like structure. The structures rationalize the mechanism of promiscuous, yet specific, drug recognition: (i) a four-ring motif present in all known TipA-inducing antibiotics is recognized specifically by conserved TipAS amino acids; and (ii) the variable part of the antibiotic is accommodated within a flexible cleft that rigidifies upon drug binding. Remarkably, the identified four-ring motif is also the major interacting part of the antibiotic with the ribosome. Hence the TipA multidrug resistance mechanism is directed against the same chemical motif that inhibits protein synthesis. The observed identity of chemical motifs responsible for antibiotic function and resistance may be a general principle and could help to better define new leads for antibiotics.
PubMed: 25489067
DOI: 10.1073/pnas.1412070111
PDB entries with the same primary citation
Experimental method
SOLUTION NMR
Structure validation

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