Center for Human Tissues and Organs Degeneration, Faculty of Pharmaceutical Sciences, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 581055, China.
Shenzhen Jingtai Technology Co., Ltd. (XtalPi), Shenzhen, 518000, China.
Nat Commun. 2024 May 11;15(1):3985. doi: 10.1038/s41467-024-48445-4.
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.
戊烷脒和喷他脒是用于治疗由寄生虫布氏锥虫引起的致命人类昏睡病的主要药物。最近，这两种药物的交叉耐药性与锥虫的水甘油通道蛋白 2（TbAQP2）有关。TbAQP2 是第一个被描述为能够进行药物运输的水通道蛋白家族成员；然而，其潜在的机制仍不清楚。在这里，我们展示了与戊烷脒或喷他脒结合的 TbAQP2 的冷冻电子显微镜结构。我们的结构研究与分子动力学模拟一起，揭示了形成底物特异性和药物渗透的机制。TbAQP2 中靠近细胞外入口和孔内的多个氨基酸形成一个扩展的传导隧道，在空间和能量上允许戊烷脒和喷他脒的渗透。我们的研究阐明了 TbAQP2 的药物转运机制，为设计针对锥虫病的药物提供了有价值的见解。
