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Transport of lipophilic carboxylates is mediated by transmembrane helix 2 in multidrug transporter AcrB

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  • Christine Oswald

    (Institute of Biochemistry, Goethe University Frankfurt
    Present address: Heptares Therapeutics, Biopark, Bradwater Road, AL7 3AX, Welwyn Garden City, Hertfordshire, UK)

  • Heng-Keat Tam

    (Institute of Biochemistry, Goethe University Frankfurt)

  • Klaas M. Pos

    (Institute of Biochemistry, Goethe University Frankfurt)

Abstract

The deployment of multidrug efflux pumps is a powerful defence mechanism for Gram-negative bacterial cells when exposed to antimicrobial agents. The major multidrug efflux transport system in Escherichia coli, AcrAB–TolC, is a tripartite system using the proton-motive force as an energy source. The polyspecific substrate-binding module AcrB uses various pathways to sequester drugs from the periplasm and outer leaflet of the inner membrane. Here we report the asymmetric AcrB structure in complex with fusidic acid at a resolution of 2.5 Å and mutational analysis of the putative fusidic acid binding site at the transmembrane domain. A groove shaped by the interface between transmembrane helix 1 (TM1) and TM2 specifically binds fusidic acid and other lipophilic carboxylated drugs. We propose that these bound drugs are actively displaced by an upward movement of TM2 towards the AcrB periplasmic porter domain in response to protonation events in the transmembrane domain.

Suggested Citation

  • Christine Oswald & Heng-Keat Tam & Klaas M. Pos, 2016. "Transport of lipophilic carboxylates is mediated by transmembrane helix 2 in multidrug transporter AcrB," Nature Communications, Nature, vol. 7(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms13819
    DOI: 10.1038/ncomms13819
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