Structure of a bacterial multidrug ABC transporter

Multidrug transporters of the ABC family facilitate the export of diverse cytotoxic drugs across cell membranes. This is clinically relevant, as tumour cells may become resistant to agents used in chemotherapy. To understand the molecular basis of this process, we have determined the 3.0 A crystal structure of a bacterial ABC transporter (Sav1866) from Staphylococcus aureus. The homodimeric protein consists of 12 transmembrane helices in an arrangement that is consistent with cross-linking studies and electron microscopic imaging of the human multidrug resistance protein MDR1, but critically different from that reported for the bacterial lipid flippase MsbA. The observed, outward-facing conformation reflects the ATP-bound state, with the two nucleotide-binding domains in close contact and the two transmembrane domains forming a central cavity—presumably the drug translocation pathway—that is shielded from the inner leaflet of the lipid bilayer and from the cytoplasm, but exposed to the outer leaflet and the extracellular space. Multidrug efflux transporters cause serious problems in cancer chemotherapy and in the treatment of bacterial infections. A puzzling aspect of their biology is how a single transporter can recognize and transport such a wide variety of structurally dissimilar compounds. The publication of the crystal structures of two quite different multidrug efflux transporters will help to solve the mystery. In the first study, the structure of AcrB — a multidrug efflux transporter from E. coli — was determined. Its three constituent subunits were captured at different steps in the transport cycle: prior to substrate binding, substrate-bound, and post-extrusion. The voluminous multidrug binding pocket handles multiple substrates via multi-site binding. The second study determined the structure of an ATP-driven multidrug transporter from S. aureus. The clinical relevance of this 'ABC' family of transporters derives from the fact that they catalyse the extrusion of various cytotoxic compounds used in cancer therapy. The structure, with the transporter in the outward-facing conformation, is a useful model of human homologues and may initiate the rational design of drugs aimed at interfering with the extrusion of agents used in chemotherapy.