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Drug export and allosteric coupling in a multidrug transporter revealed by molecular simulations

Author

Listed:
  • Xin-Qiu Yao

    (Graduate School of Science, Kyoto University)

  • Hiroo Kenzaki

    (Graduate School of Science, Kyoto University)

  • Satoshi Murakami

    (CREST, Japan Science and Technology Agency
    School and Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology)

  • Shoji Takada

    (Graduate School of Science, Kyoto University
    CREST, Japan Science and Technology Agency
    Advanced Center for Computing and Communication, RIKEN, Wako, Saitama 351-0198, Japan.)

Abstract

Multidrug resistance is a serious problem in current chemotherapy. The efflux system largely responsible for resistance in Escherichia coli contains the drug transporter, AcrB. The structures of AcrB were solved in 2002 as the symmetric homo-trimer, and then in 2006 as the asymmetric homo-trimer. The latter suggested a functionally rotating mechanism. Here, by molecular simulations of the AcrB porter domain, we uncovered allosteric coupling and the drug export mechanism in the AcrB trimer. Allosteric coupling stabilized the asymmetric structure with one drug molecule bound, which validated the modelling. Drug dissociation caused a conformational change and stabilized the symmetric structure, providing a unified view of the structures reported in 2002 and 2006. A dynamic study suggested that, among the three potential driving processes, only protonation of the drug-bound protomer can drive the functional rotation and simultaneously export the drug.

Suggested Citation

  • Xin-Qiu Yao & Hiroo Kenzaki & Satoshi Murakami & Shoji Takada, 2010. "Drug export and allosteric coupling in a multidrug transporter revealed by molecular simulations," Nature Communications, Nature, vol. 1(1), pages 1-8, December.
    • Handle: RePEc:nat:natcom:v:1:y:2010:i:1:d:10.1038_ncomms1116
    DOI: 10.1038/ncomms1116
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    Cited by:

    1. Yong Wang & Chun Tang & Erkang Wang & Jin Wang, 2012. "Exploration of Multi-State Conformational Dynamics and Underlying Global Functional Landscape of Maltose Binding Protein," PLOS Computational Biology, Public Library of Science, vol. 8(4), pages 1-15, April.

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