Crystal structure of the TetR/CamR family repressor Mycobacterium tuberculosis EthR implicated in ethionamide resistance

Lynn G. Dover, Patrick E. Corsino, Ian R. Daniels, Sarah L. Cocklin, Vijaya Tatituri, Gurdyal S. Besra, Klaus Fütterer*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

92 Citations (Scopus)

Abstract

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 1.7Å resolution, revealing a dimeric two-domain molecule with an overall architecture typical for TetR/CamR repressor proteins. A 20Å 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.

Original languageEnglish
Pages (from-to)1095-1105
Number of pages11
JournalJournal of Molecular Biology
Volume340
Issue number5
DOIs
Publication statusPublished - 23 Jul 2004
Externally publishedYes

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