Crystal structure of the TetR/Cam R family repressor Mycobacterium tuberculosis EthR implicated in ethionamide resistance
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Colleges, School and Institutes
Ethionamide has been used for more than 30 years as a second-line chemotherapeutic to treat tuberculosis patients who have developed resistance to first-line drugs, such as isoniazid (INH) and rifampicin. Activation of the pro-drug ethionamide is regulated by the Baeyer-Villiger monooxygenase EthA and the TetR/CamR family repressor EthR, whose open reading frames are separated by 75 bp on the Mycobacterium tuberculosis genome. EthR has been shown to repress transcription of the activator gene ethA by binding to this intergenic region, thus contributing to ethionamide resistance. We have determined the crystal structure of EthR, to 1.7 Angstrom resolution, revealing a dimeric twodomain molecule with an overall architecture typical for TetR/CamR repressor proteins. A 20 Angstrom long hydrophobic tunnel-like cavity in the "drug-binding" domain of EthR is occupied by two 1,4-dioxane molecules, a component of the crystallisation buffer. Comparing the present structure to those of the homologues Staphylococcus aureus QacR and Escherichia coli TetR leads to the hypothesis that the hydrophobic cavity constitutes a binding site for an as yet unknown ligand that might regulate DNA-binding of EthR. (C) 2004 Elsevier Ltd. All rights reserved.
|Number of pages||11|
|Journal||Journal of Molecular Biology|
|Publication status||Published - 1 Jan 2004|
- X-ray crystallography, TetR family, helix-turn-helix, ethionamide, Mycobacterium tuberculosis