The efflux of multiple drugs by Mdr transporters represents a major obstacle to successfully treating cancer and infectious diseases. In addition to their clinical importance, Mdr transporters attracted us because they have intriguing mechanistic characteristics that differ substantially from those of substrate-specific transport systems (Fluman and Bibi, 2009). Collectively, our studies of the E. coli secondary Mdr transporter MdfA demonstrated that in order for these transporters to function in multidrug resistance, they must be exceptionally flexible in structure and function. As major goals for the future, we hope to: (1) Solve the high-resolution 3D structure of MdfA and (2) elucidate the multidrug transport mechanism, with an emphasis on the novel proton recognition and translocation mechanism.
Theoretical 3D model of the secondary multidrug transporter MdfA.
Left panel, side view. Right panel, a view into the proposed multidrug binding pocket with the native essential acidic residues (E26 and D34) shown in magenta and the acidic residues that were inserted as a result of selective genetic screens (at positions 150, 335, or 354) are shown in red.