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Structures of the Mycobacterium tuberculosis efflux pump EfpA reveal the mechanisms of transport and inhibition

Author

Listed:
  • Shuhui Wang

    (Harvard Medical School
    Yale University)

  • Kun Wang

    (Harvard Medical School
    Harvard T.H. Chan School of Public Health)

  • Kangkang Song

    (University of Massachusetts Chan Medical School
    University of Massachusetts Chan Medical School)

  • Zon Weng Lai

    (Harvard T.H. Chan School of Public Health
    Sanofi)

  • Pengfei Li

    (LLC)

  • Dongying Li

    (Harvard Medical School
    Southern University of Science and Technology)

  • Yajie Sun

    (Huazhong University of Science and Technology)

  • Ye Mei

    (East China Normal University)

  • Chen Xu

    (University of Massachusetts Chan Medical School
    University of Massachusetts Chan Medical School)

  • Maofu Liao

    (Southern University of Science and Technology
    Southern University of Science and Technology)

Abstract

As the first identified multidrug efflux pump in Mycobacterium tuberculosis (Mtb), EfpA is an essential protein and promising drug target. However, the functional and inhibitory mechanisms of EfpA are poorly understood. Here we report cryo-EM structures of EfpA in outward-open conformation, either bound to three endogenous lipids or the inhibitor BRD-8000.3. Three lipids inside EfpA span from the inner leaflet to the outer leaflet of the membrane. BRD-8000.3 occupies one lipid site at the level of inner membrane leaflet, competitively inhibiting lipid binding. EfpA resembles the related lysophospholipid transporter MFSD2A in both overall structure and lipid binding sites and may function as a lipid flippase. Combining AlphaFold-predicted EfpA structure, which is inward-open, we propose a complete conformational transition cycle for EfpA. Together, our results provide a structural and mechanistic foundation to comprehend EfpA function and develop EfpA-targeting anti-TB drugs.

Suggested Citation

  • Shuhui Wang & Kun Wang & Kangkang Song & Zon Weng Lai & Pengfei Li & Dongying Li & Yajie Sun & Ye Mei & Chen Xu & Maofu Liao, 2024. "Structures of the Mycobacterium tuberculosis efflux pump EfpA reveal the mechanisms of transport and inhibition," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51948-9
    DOI: 10.1038/s41467-024-51948-9
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