Crystal structure of the transcription activator BmrR bound to DNA and a drug

The efflux of chemically diverse drugs by multidrug transporters that span the membrane(1) is one mechanism of multidrug resistance in bacteria. The c oncentrations of many of these transporters are controlled by transcription regulators, such as BmrR in Bacillus subtilis(2), EmrR in Escherichia coli (3) and QacR in Staphylococcus aureus(4). These proteins promote transporte r gene expression when they bind toxic compounds. BmrR activates transcript ion of the multidrug transporter gene, bmr, in response to cellular invasio n by certain lipophilic cationic compounds (drugs)(2,5,6). BmrR belongs to the MerR family, which regulates response to stress such as exposure to tox ic compounds or oxygen radicals in bacteria(7-12). MerR proteins have homol ogous aminoterminal DNA-binding domains but different carboxy-terminal doma ins, which enable them to bind specific 'coactivator' molecules. When bound to coactivator, MerR proteins upregulate transcription by reconfiguring th e 19-base-pair spacer found between the -35 and -10 promoter elements to al low productive interaction with RNA polymerase(7,9-12). Here we report the 3.0 Angstrom resolution structure of BmrR in complex with the drug tetraphe nylphosphonium (TPP) and a 22-base-pair oligodeoxynucleotide encompassing t he bmr promoter. The structure reveals an unexpected mechanism for transcri ption activation that involves localized base-pair breaking, and base slidi ng and realignment of the -35 and -10 operator elements.