1U9N: Crystal Structure Of The Transcriptional Regulator Ethr In A Ligand Bound Conformation Opens Therapeutic Perspectives Against Tuberculosis And Leprosy

Citation:
Abstract
Mycobacterium tuberculosis EthR is a repressor of ethA, a gene encoding a mono-oxygenase required for the activation of the prodrug ethionamide. Here we describe the X-ray crystal structure of EthR, a homodimer with an entirely helical structure showing similarities to TetR family members. Each monomer contained a fortuitous ligand identified as hexadecyl octanoate. The crystal structure of EthR purified in M. smegmatis revealed the presence of a comparable ligand. The binding of hexadecyl octanoate to EthR induces a conformational state incompatible with repressor function, which should lead to ethA derepression and consequently to an increased sensitivity to ethionamide and other thioamides. A related, more hydrophilic ketone was found to exhibit synergistic antimycobacterial effects when tested together with ethionamide, indicating that this strategy may help reduce the dosage of potent antibacterial compounds that otherwise are too toxic to be used as first-line drugs.
PDB ID: 1U9NDownload
MMDB ID: 30378
PDB Deposition Date: 2004/8/10
Updated in MMDB: 2007/10
Experimental Method:
x-ray diffraction
Resolution: 2.3  Å
Source Organism:
Similar Structures:
Biological Unit for 1U9N: dimeric; determined by author
Molecular Components in 1U9N
Label Count Molecule
Proteins (2 molecules)
2
Transcriptional Repressor Ethr
Molecule annotation
Chemicals (2 molecules)
1
2
* Click molecule labels to explore molecular sequence information.

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