2. Academic Validation
  3. Structural insights into drug transport by an aquaglyceroporin

Structural insights into drug transport by an aquaglyceroporin

  • Nat Commun. 2024 May 11;15(1):3985. doi: 10.1038/s41467-024-48445-4.
Wanbiao Chen # 1,  Rongfeng Zou # 2,  Yi Mei # 3 4 5,  Jiawei Li 1 6,  Yumi Xuan 1,  Bing Cui 1 7,  Junjie Zou 2,  Juncheng Wang 8,  Shaoquan Lin 9,  Zhe Zhang 10 11 12,  Chongyuan Wang 13
Affiliations

Affiliations

  • 1 Center for Human Tissues and Organs Degeneration, Faculty of Pharmaceutical Sciences, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 581055, China.
  • 2 Shenzhen Jingtai Technology Co., Ltd. (XtalPi), Shenzhen, 518000, China.
  • 3 Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221004, China.
  • 4 Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221004, China.
  • 5 NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221004, China.
  • 6 Department of Geriatric Medicine, Shenzhen Longhua District Central Hospital, Shenzhen, 518110, China.
  • 7 School of Basic Medicine and Clinical Pharmacy, and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China.
  • 8 Advanced Medical Research Institute, Shandong University, Jinan, China.
  • 9 Centre for Polymers in Medicine, Faculty of Pharmaceutical Sciences, Shenzhen Institute of Advanced Technology, Chinese Academy of Science, Shenzhen, 581055, China.
  • 10 Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221004, China. zhangzhe70@xzhmu.edu.cn.
  • 11 Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221004, China. zhangzhe70@xzhmu.edu.cn.
  • 12 NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221004, China. zhangzhe70@xzhmu.edu.cn.
  • 13 Center for Human Tissues and Organs Degeneration, Faculty of Pharmaceutical Sciences, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 581055, China. cy.wang@siat.ac.cn.
  • # Contributed equally.
PMID: 38734677 DOI: 10.1038/s41467-024-48445-4
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.

Figures
Products