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Structure of a bacterial multidrug ABC transporter

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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Figure 1: Sav1866 structure.
Figure 2: Superposition of nucleotide-binding domain structures.
Figure 3: Transmission interface.
Figure 5: ABC exporter schematics.
Figure 4: Substrate translocation pathway.

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Acknowledgements

We thank C. Schulze-Briese, E. Pohl and T. Tomizaki for assistance with synchrotron data collection, D. Sargent for help with xenon derivatization, and J. Rosenbusch for critical reading of the manuscript. This work was supported by the Roche Research Fund, the NCCR Structural Biology Zurich, the Swiss National Science Foundation, and the Swiss Cancer League Oncosuisse.

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Correspondence to Kaspar P. Locher.

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Coordinates and structure factors for Sav1866 have been deposited in the Protein Data Bank under the accession code 2HYD. Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.

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This file contains Supplementary Methods, Supplementary references, Supplementary Tables 1 and 2, and Supplementary Figures 1–4. (DOC 9821 kb)

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Dawson, R., Locher, K. Structure of a bacterial multidrug ABC transporter. Nature 443, 180–185 (2006). https://doi.org/10.1038/nature05155

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