A structure-based mechanism for drug binding by multidrug transporters

Multidrug transporters bind chemically dissimilar, potentially cytotoxic co mpounds and remove them from the cell. How these transporters carry out eit her of these functions is unknown. On the basis of crystal structures of th e multidrug-binding domain of the transcription activator BmrR and mutagene sis studies on the bacterial multidrug transporter MdfA, we propose a possi ble mechanism for the binding of cationic lipophilic drugs by multidrug tra nsporters, The key element of this mechanism includes a conformational chan ge in the transporter that exposes a buried charged residue in the substrat e-binding pocket and allows access to this site by only those drugs that ar e its steric and electrostatic complements.