Structural basis for antibiotic recognition by the TipA class of multidrug-resistance transcriptional regulators

The TipAL protein, a bacterial transcriptional regulator of the MerR family, is activated by numerous cyclic thiopeptide antibiotics. Its C‐terminal drug‐binding domain, TipAS, defines a subfamily of broadly distributed bacterial proteins including Mta, a central regulator of multidrug resistance in...

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Bibliographic Details
Published in:The EMBO journal 2003-04, Vol.22 (8), p.1824-1834
Main Authors: Kahmann, Jan D., Sass, Hans-Jürgen, Allan, Martin G., Seto, Haruo, Thompson, Charles J., Grzesiek, Stephan
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Anti-Bacterial Agents - chemistry
Anti-Bacterial Agents - metabolism
antibiotic recognition
Antibiotics
Bacterial Proteins - chemistry
Bacterial Proteins - genetics
Bacterial Proteins - metabolism
Binding Sites
Drug resistance
Drug Resistance, Multiple - physiology
EMBO24
EMBO40
globin fold
heteronuclear NMR
Ligands
Models, Molecular
Molecular Sequence Data
Molecular Structure
Nuclear Magnetic Resonance, Biomolecular
protein dynamics
Protein Folding
Protein Structure, Secondary
Protein Structure, Tertiary
Sequence Alignment
Structure-Activity Relationship
Trans-Activators - chemistry
Trans-Activators - genetics
Trans-Activators - metabolism
transcriptional regulation
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Summary:The TipAL protein, a bacterial transcriptional regulator of the MerR family, is activated by numerous cyclic thiopeptide antibiotics. Its C‐terminal drug‐binding domain, TipAS, defines a subfamily of broadly distributed bacterial proteins including Mta, a central regulator of multidrug resistance in Bacillus subtilis . The structure of apo TipAS, solved by solution NMR [Brookhaven Protein Data Bank entry 1NY9], is composed of a globin‐like α‐helical fold with a deep surface cleft and an unfolded N‐terminal region. Antibiotics bind within the cleft at a position that is close to the corresponding heme pocket in myo‐ and hemoglobin, and induce folding of the N‐terminus. Thus the classical globin fold is well adapted not only for accommodating its canonical cofactors, heme and other tetrapyrroles, but also for the recognition of a variety of antibiotics where ligand binding leads to transcriptional activation and drug resistance.
ISSN:0261-4189
1460-2075
1460-2075
DOI:10.1093/emboj/cdg181