8JY7

Structure of the TbAQP2 in the apo conformation

Summary for 8JY7

• Entry DOI: 10.2210/pdb8jy7/pdb
• EMDB information: 36722
• Descriptor: Aquaglyceroporin 2 (1 entity in total)
• Functional Keywords: aquaporin, membrane protein
• Biological source: Trypanosoma brucei brucei
• Total number of polymer chains: 4
• Total formula weight: 147103.66

Authors

Chen, W.,Wang, C. (deposition date: 2023-07-03, release date: 2024-05-29)

Primary citation

Chen, W.,Zou, R.,Mei, Y.,Li, J.,Xuan, Y.,Cui, B.,Zou, J.,Wang, J.,Lin, S.,Zhang, Z.,Wang, C.
Structural insights into drug transport by an aquaglyceroporin.
Nat Commun, 15:3985-3985, 2024

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.

PubMed: 38734677
DOI: 10.1038/s41467-024-48445-4

Experimental method

ELECTRON MICROSCOPY (3.2 Å)