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 Bacillus subtilis. The structure of apo TipAS, solved by solution NMR [Brookhaven Protein Data Bank entry 1NY9], is composed of a globin-like alpha-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.
Kahmann
Jan D
JD
Division of Structural Biology, Biozentrum der Universität Basel, Klingelbergstrasse 70, CH-4056 Basel, Switzerland.
Sass
Hans-Jürgen
HJ
Allan
Martin G
MG
Seto
Haruo
H
Thompson
Charles J
CJ
Grzesiek
Stephan
S
D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000378:metabolism; D001426:Bacterial Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D018432:Drug Resistance, Multiple / Q000502:physiology*; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D013329:Structure-Activity Relationship; D015534:Trans-Activators / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; C098722:BmrR protein, bacteria; D008024:Ligands; C119773:Mta protein, Bacillus subtilis; C082535:TipAL protein, Streptomyces; D015534:Trans-Activators; C082536:tipAS protein, Streptomyces