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 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.