Role of Aromatic and Negatively Charged Residues of DrrB in Multisubstrate Specificity Conferred by the DrrAB System of Streptomyces peucetius

Resistance to the anticancer antibiotics, doxorubicin and daunorubicin, in the producer organism Streptomyces peucetius is conferred by an ABC transporter made of two proteins, DrrA and DrrB, which together form a dedicated exporter for these two antibiotics. Surprisingly, however, the DrrAB system exhibits broad substrate specificity overlapping with well-studied multidrug resistance transporters, including P-glycoprotein. Therefore, it provides an excellent model for studying the molecular basis of multispecificity in a prototype efflux system with the potential to unravel the origin and evolution of multidrug resistance. It has been suggested that multispecificity in multidrug exporters may be generally determined by the number and location of aromatic residues. Strategically placed negatively charged residues may also be critical for binding of cationic lipophilic drugs. We selected 13 aromatic and four negatively charged residues on the basis of their location in and/or near the predicted drug-bindin...