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

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F60077344%3A_____%2F20%3A00535601" target="_blank" >RIV/60077344:_____/20:00535601 - isvavai.cz</a>

Result on the web

<a href="https://elifesciences.org/articles/56416" target="_blank" >https://elifesciences.org/articles/56416</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.7554/eLife.56416" target="_blank" >10.7554/eLife.56416</a>

Result language

angličtina

Original language name

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

Original language description

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.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

10606 - Microbiology

Project

—

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2020

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

eLife

ISSN

2050-084X

e-ISSN

—

Volume of the periodical

9

Issue of the periodical within the volume

AUG 11 2020

Country of publishing house

GB - UNITED KINGDOM

Number of pages

33

Pages from-to

e56416

UT code for WoS article

000569334500001

EID of the result in the Scopus database

2-s2.0-85090297368