Insights from aquaporin structures into drug-resistant sleeping sickness.

ABSTRACT: Trypanosoma brucei is the causal agent of African trypanosomiasis in humans and animals, the latter resulting in significant negative economic impacts in afflicted areas of the world. Resistance has arisen to the trypanocidal drugs pentamidine and melarsoprol through mutations in the aquaglyceroporin TbAQP2 that prevent their uptake. Here, we use cryogenic electron microscopy to determine the structure of TbAQP2 from T. brucei, bound to either the substrate glycerol or to the sleeping sickness drugs, pentamidine or melarsoprol. The drugs bind within the AQP2 channel at a site completely overlapping that of glycerol. Mutations leading to a drug-resistant phenotype were found in the channel lining. Molecular dynamics (MD) simulations showed the channel can be traversed by penta

SUBMITTER: Matusevicius M 

PROVIDER: S-EPMC12803511 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature