Structural basis of multidrug recognition by BmrR, a transcription activator of a multidrug transporter

Multidrug-efflux transporters demonstrate an unusual ability to recognize m ultiple structurally dissimilar toxins. A comparable ability to bind divers e hydrophobic cationic drugs is characteristic of the Bacillus subtilis tra nscription regulator BmrR, which upon drug binding activates expression of the multidrug transporter Bmr. Crystal structures of the multidrug-binding domain of BmrR (2.7 Angstrom resolution) and of its complex with the drug t etraphenylphosphonium (2.8 Angstrom resolution) revealed a drug-induced unf olding and relocation of an alpha helix, which exposes an internal drug-bin ding pocket. Tetraphenylphosphonium binding is mediated by stacking and van der Waals contacts with multiple hydrophobic residues of the pocket and by an electrostatic interaction between the positively charged drug and a bur ied glutamate residue, which is the key to cation selectivity. Similar bind ing principles may be used by other multidrug-binding proteins.