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Inhibition of M. tuberculosis and human ATP synthase by BDQ and TBAJ-587

Author

Listed:
  • Yuying Zhang

    (Nankai University)

  • Yuezheng Lai

    (Nankai University)

  • Shan Zhou

    (Nankai University)

  • Ting Ran

    (Guangzhou National Laboratory)

  • Yue Zhang

    (Nankai University)

  • Ziqing Zhao

    (Nankai University)

  • Ziyan Feng

    (Nankai University)

  • Long Yu

    (Nankai University)

  • Jinxu Xu

    (Nankai University)

  • Kun Shi

    (Nankai University)

  • Jianyun Wang

    (Nankai University)

  • Yu Pang

    (Capital Medical University)

  • Liang Li

    (Capital Medical University)

  • Hongming Chen

    (Guangzhou National Laboratory)

  • Luke W. Guddat

    (University of Queensland)

  • Yan Gao

    (ShanghaiTech University)

  • Fengjiang Liu

    (Guangzhou National Laboratory)

  • Zihe Rao

    (Nankai University
    Guangzhou National Laboratory
    ShanghaiTech University
    Tsinghua University)

  • Hongri Gong

    (Nankai University)

Abstract

Bedaquiline (BDQ), a first-in-class diarylquinoline anti-tuberculosis drug, and its analogue, TBAJ-587, prevent the growth and proliferation of Mycobacterium tuberculosis by inhibiting ATP synthase1,2. However, BDQ also inhibits human ATP synthase3. At present, how these compounds interact with either M. tuberculosis ATP synthase or human ATP synthase is unclear. Here we present cryogenic electron microscopy structures of M. tuberculosis ATP synthase with and without BDQ and TBAJ-587 bound, and human ATP synthase bound to BDQ. The two inhibitors interact with subunit a and the c-ring at the leading site, c-only sites and lagging site in M. tuberculosis ATP synthase, showing that BDQ and TBAJ-587 have similar modes of action. The quinolinyl and dimethylamino units of the compounds make extensive contacts with the protein. The structure of human ATP synthase in complex with BDQ reveals that the BDQ-binding site is similar to that observed for the leading site in M. tuberculosis ATP synthase, and that the quinolinyl unit also interacts extensively with the human enzyme. This study will improve researchers’ understanding of the similarities and differences between human ATP synthase and M. tuberculosis ATP synthase in terms of the mode of BDQ binding, and will allow the rational design of novel diarylquinolines as anti-tuberculosis drugs.

Suggested Citation

  • Yuying Zhang & Yuezheng Lai & Shan Zhou & Ting Ran & Yue Zhang & Ziqing Zhao & Ziyan Feng & Long Yu & Jinxu Xu & Kun Shi & Jianyun Wang & Yu Pang & Liang Li & Hongming Chen & Luke W. Guddat & Yan Gao , 2024. "Inhibition of M. tuberculosis and human ATP synthase by BDQ and TBAJ-587," Nature, Nature, vol. 631(8020), pages 409-414, July.
  • Handle: RePEc:nat:nature:v:631:y:2024:i:8020:d:10.1038_s41586-024-07605-8
    DOI: 10.1038/s41586-024-07605-8
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