PDF(Pubmed)
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.
摘要：
Pentamidine和melarsoprol是用于治疗由寄生虫锥虫引起的致命人类昏睡病的主要药物。对这两种药物的交叉抗性最近与锥虫的aquaglyceroporin2（TbAQP2）有关。TbAQP2是水通道蛋白家族的第一个成员，被描述为能够运输药物；然而，潜在机制尚不清楚.这里,我们介绍了与喷他脒或美洛醇结合的TbAQP2的低温电子显微镜结构。我们的结构研究，连同分子动力学模拟，揭示了形成底物特异性和药物渗透的机制。TbAQP2中的多个氨基酸，靠近细胞外入口和孔内，创建一个扩展的导电隧道，在空间和能量上允许戊脒和美拉洛尔的渗透。我们的研究阐明了TbAQP2的药物转运机制，为设计抗锥虫病药物提供了有价值的见解。
