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Structure of a bacterial multidrug ABC transporter

Author

Listed:
  • Roger J. P. Dawson

    (Institute of Molecular Biology and Biophysics, ETH Zurich)

  • Kaspar P. Locher

    (Institute of Molecular Biology and Biophysics, ETH Zurich)

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.

Suggested Citation

  • Roger J. P. Dawson & Kaspar P. Locher, 2006. "Structure of a bacterial multidrug ABC transporter," Nature, Nature, vol. 443(7108), pages 180-185, September.
  • Handle: RePEc:nat:nature:v:443:y:2006:i:7108:d:10.1038_nature05155
    DOI: 10.1038/nature05155
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    Cited by:

    1. Tianqi Zhang & Jixing Lyu & Bowei Yang & Sangho D. Yun & Elena Scott & Minglei Zhao & Arthur Laganowsky, 2024. "Native mass spectrometry and structural studies reveal modulation of MsbA–nucleotide interactions by lipids," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    2. Lin Yu & Xin Xu & Wan-Zhen Chua & Hao Feng & Zheng Ser & Kai Shao & Jian Shi & Yumei Wang & Zongli Li & Radoslaw M. Sobota & Lok-To Sham & Min Luo, 2023. "Structural basis of peptide secretion for Quorum sensing by ComA," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    3. Adrian W R Serohijos & Tamás Hegedűs & John R Riordan & Nikolay V Dokholyan, 2008. "Diminished Self-Chaperoning Activity of the ΔF508 Mutant of CFTR Results in Protein Misfolding," PLOS Computational Biology, Public Library of Science, vol. 4(2), pages 1-8, February.
    4. Sheng Cao & Yihu Yang & Lili He & Yumo Hang & Xiaodong Yan & Hui Shi & Jiaquan Wu & Zhuqing Ouyang, 2023. "Cryo-EM structures of mitochondrial ABC transporter ABCB10 in apo and biliverdin-bound form," Nature Communications, Nature, vol. 14(1), pages 1-9, December.
    5. Jere P. Segrest & Chongren Tang & Hyun D. Song & Martin K. Jones & W. Sean Davidson & Stephen G. Aller & Jay W. Heinecke, 2022. "ABCA1 is an extracellular phospholipid translocase," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    6. Ruojing Zhang & Kevin L. Jagessar & Matthew Brownd & Adithya Polasa & Richard A. Stein & Mahmoud Moradi & Erkan Karakas & Hassane S. Mchaourab, 2024. "Conformational cycle of a protease-containing ABC transporter in lipid nanodiscs reveals the mechanism of cargo-protein coupling," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    7. Megan L O’Mara & Alan E Mark, 2014. "Structural Characterization of Two Metastable ATP-Bound States of P-Glycoprotein," PLOS ONE, Public Library of Science, vol. 9(3), pages 1-14, March.

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