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Structural insights into drug transport by an aquaglyceroporin

Author

Listed:
  • Wanbiao Chen

    (Chinese Academy of Sciences)

  • Rongfeng Zou

    (Ltd. (XtalPi))

  • Yi Mei

    (Xuzhou Medical University
    Xuzhou Medical University
    Xuzhou Medical University)

  • Jiawei Li

    (Chinese Academy of Sciences
    Shenzhen Longhua District Central Hospital)

  • Yumi Xuan

    (Chinese Academy of Sciences)

  • Bing Cui

    (Chinese Academy of Sciences
    China Pharmaceutical University)

  • Junjie Zou

    (Ltd. (XtalPi))

  • Juncheng Wang

    (Shandong University)

  • Shaoquan Lin

    (Shenzhen Institute of Advanced Technology, Chinese Academy of Science)

  • Zhe Zhang

    (Xuzhou Medical University
    Xuzhou Medical University
    Xuzhou Medical University)

  • Chongyuan Wang

    (Chinese Academy of Sciences)

Abstract

Pentamidine and melarsoprol are primary drugs used to treat the lethal human sleeping sickness caused by the parasite Trypanosoma brucei. Cross-resistance to these two drugs has recently been linked to aquaglyceroporin 2 of the trypanosome (TbAQP2). TbAQP2 is the first member of the aquaporin family described as capable of drug transport; however, the underlying mechanism remains unclear. Here, we present cryo-electron microscopy structures of TbAQP2 bound to pentamidine or melarsoprol. Our structural studies, together with the molecular dynamic simulations, reveal the mechanisms shaping substrate specificity and drug permeation. Multiple amino acids in TbAQP2, near the extracellular entrance and inside the pore, create an expanded conducting tunnel, sterically and energetically allowing the permeation of pentamidine and melarsoprol. Our study elucidates the mechanism of drug transport by TbAQP2, providing valuable insights to inform the design of drugs against trypanosomiasis.

Suggested Citation

  • Wanbiao Chen & Rongfeng Zou & Yi Mei & Jiawei Li & Yumi Xuan & Bing Cui & Junjie Zou & Juncheng Wang & Shaoquan Lin & Zhe Zhang & Chongyuan Wang, 2024. "Structural insights into drug transport by an aquaglyceroporin," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48445-4
    DOI: 10.1038/s41467-024-48445-4
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    References listed on IDEAS

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    1. Yuriy Kirichok & Grigory Krapivinsky & David E. Clapham, 2004. "The mitochondrial calcium uniporter is a highly selective ion channel," Nature, Nature, vol. 427(6972), pages 360-364, January.
    2. Kazuyoshi Murata & Kaoru Mitsuoka & Teruhisa Hirai & Thomas Walz & Peter Agre & J. Bernard Heymann & Andreas Engel & Yoshinori Fujiyoshi, 2000. "Structural determinants of water permeation through aquaporin-1," Nature, Nature, vol. 407(6804), pages 599-605, October.
    3. Sam Alsford & Sabine Eckert & Nicola Baker & Lucy Glover & Alejandro Sanchez-Flores & Ka Fai Leung & Daniel J. Turner & Mark C. Field & Matthew Berriman & David Horn, 2012. "High-throughput decoding of antitrypanosomal drug efficacy and resistance," Nature, Nature, vol. 482(7384), pages 232-236, February.
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