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  • The EMBO Journal (2003) 22, 1824 - 1834
  • doi:10.1093/emboj/cdg181

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

Jan D. Kahmann1, Hans-Jürgen Sass1, Martin G. Allan1, Haruo Seto2, Charles J. Thompson3 and Stephan Grzesiek1

  1. Division of Structural Biology, Biozentrum der Universität Basel, Klingelbergstrasse 70, CH-4056 Basel, Switzerland
  2. Department of Applied Biology and Chemistry, Faculty of Applied Bio-Science, Tokyo University of Agriculture, Tokyo, Japan
  3. Division of Microbiology, Biozentrum der Universität Basel, Klingelbergstrasse 70, CH-4056 Basel, Switzerland

Correspondence to:

Hans-Jürgen Sass, E-mail: juergen.sass@unibas.ch

Charles J. Thompson, E-mail: charles-j.thompson@unibas.ch

Stephan Grzesiek, E-mail: stephan.grzesiek@unibas.ch

Received 18 December 2002; Accepted 24 February 2003; Revised 21 February 2003

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.

  • Keywords:

    • antibiotic recognition,
    • globin fold,
    • heteronuclear NMR,
    • protein dynamics,
    • transcriptional regulation