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Positively selected modifications in the pore of TbAQP2 allow pentamidine to enter Trypanosoma brucei

AH. Alghamdi, JC. Munday, GD. Campagnaro, D. Gurvic, F. Svensson, CE. Okpara, A. Kumar, J. Quintana, ME. Martin Abril, P. Milić, L. Watson, D. Paape, L. Settimo, A. Dimitriou, J. Wielinska, G. Smart, LF. Anderson, CM. Woodley, SPY. Kelly, HM....

. 2020 ; 9 (-) : . [pub] 20200811

Jazyk angličtina Země Velká Británie

Typ dokumentu časopisecké články, Research Support, N.I.H., Extramural, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc21012272

Grantová podpora
GM111749 NIH HHS - United States
204697/Z/16/Z Wellcome - International
206385/2014-5 Science Without Borders, Brazil - International
84733 Medical Research Council - United Kingdom
Wellcome Trust - United Kingdom
R01 GM111749 NIGMS NIH HHS - United States
MR/R015791/1 Medical Research Council - United Kingdom
G0701258 Medical Research Council - United Kingdom

Mutations in the Trypanosoma brucei aquaporin AQP2 are associated with resistance to pentamidine and melarsoprol. We show that TbAQP2 but not TbAQP3 was positively selected for increased pore size from a common ancestor aquaporin. We demonstrate that TbAQP2's unique architecture permits pentamidine permeation through its central pore and show how specific mutations in highly conserved motifs affect drug permeation. Introduction of key TbAQP2 amino acids into TbAQP3 renders the latter permeable to pentamidine. Molecular dynamics demonstrates that permeation by dicationic pentamidine is energetically favourable in TbAQP2, driven by the membrane potential, although aquaporins are normally strictly impermeable for ionic species. We also identify the structural determinants that make pentamidine a permeant although most other diamidine drugs are excluded. Our results have wide-ranging implications for optimising antitrypanosomal drugs and averting cross-resistance. Moreover, these new insights in aquaporin permeation may allow the pharmacological exploitation of other members of this ubiquitous gene family.

Citace poskytuje Crossref.org

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