Structural insights into drug transport by an aquaglyceroporin

Wanbiao Chen, Rongfeng Zou, Yi Mei, Jiawei Li, Yumi Xuan, Bing Cui, Junjie Zou, Juncheng Wang, Shaoquan Lin, Zhe Zhang () and Chongyuan Wang ()
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Wanbiao Chen: Chinese Academy of Sciences
Rongfeng Zou: Ltd. (XtalPi)
Yi Mei: Xuzhou Medical University
Jiawei Li: Chinese Academy of Sciences
Yumi Xuan: Chinese Academy of Sciences
Bing Cui: Chinese Academy of Sciences
Junjie Zou: Ltd. (XtalPi)
Juncheng Wang: Shandong University
Shaoquan Lin: Shenzhen Institute of Advanced Technology, Chinese Academy of Science
Zhe Zhang: Xuzhou Medical University
Chongyuan Wang: Chinese Academy of Sciences

Nature Communications, 2024, vol. 15, issue 1, 1-10

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-48445-4

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