1. Institute of Molecular Biology and Biophysics, ETH Zurich, 8093 Zurich, Switzerland

Correspondence to: Kaspar P. Locher¹ Correspondence and requests for materials should be addressed to K.P.L. (Email: kaspar.locher@mol.biol.ethz.ch). Coordinates and structure factors for Sav1866 have been deposited in the Protein Data Bank under the accession code 2HYD.

Abstract

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 Å 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.

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