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dc.contributor.authorAlghamdi, Ali H
dc.contributor.authorMunday, Jane C
dc.contributor.authorCampagnaro, Gustavo Daniel
dc.contributor.authorGurvic, Dominik
dc.contributor.authorSvensson, Fredrik
dc.contributor.authorOkpara, Chinyere E
dc.contributor.authorKumar, Arvind
dc.contributor.authorQuintana, Juan
dc.contributor.authorMartin Abril, Maria Esther
dc.contributor.authorMilić, Patrik
dc.contributor.authorWatson, Laura
dc.contributor.authorPaape, Daniel
dc.contributor.authorSettimo, Luca
dc.contributor.authorDimitriou, Anna
dc.contributor.authorWielinska, Joanna
dc.contributor.authorSmart, Graeme
dc.contributor.authorAnderson, Laura F
dc.contributor.authorWoodley, Christopher M
dc.contributor.authorKelly, Siu Pui Ying
dc.contributor.authorIbrahim, Hasan MS
dc.contributor.authorHulpia, Fabian
dc.contributor.authorAl-Salabi, Mohammed I
dc.contributor.authorEze, Anthonius A
dc.contributor.authorSprenger, Teresa
dc.contributor.authorTeka, Ibrahim A
dc.contributor.authorGudin, Simon
dc.contributor.authorWeyand, Simone
dc.contributor.authorField, Mark
dc.contributor.authorDardonville, Christophe
dc.contributor.authorTidwell, Richard R
dc.contributor.authorCarrington, Mark
dc.contributor.authorO'Neill, Paul
dc.contributor.authorBoykin, David W
dc.contributor.authorZachariae, Ulrich
dc.contributor.authorDe Koning, Harry P
dc.date.accessioned2020-09-05T05:11:47Z
dc.date.available2020-09-05T05:11:47Z
dc.date.issued2020-08-11
dc.date.submitted2020-02-26
dc.identifier.other56416
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/309952
dc.descriptionFunder: Scottish Universities Physics Alliance; FundRef: http://dx.doi.org/10.13039/501100000708
dc.descriptionFunder: Albaha University
dc.descriptionFunder: Medical Research Council; FundRef: http://dx.doi.org/10.13039/501100000265
dc.descriptionFunder: Cambridge trust
dc.descriptionFunder: Wellcome Trust; FundRef: http://dx.doi.org/10.13039/100004440
dc.descriptionFunder: Royal Society; FundRef: http://dx.doi.org/10.13039/501100000288
dc.description.abstractMutations 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.
dc.languageen
dc.publishereLife Sciences Publications, Ltd
dc.rightsAttribution 4.0 International (CC BY 4.0)en
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en
dc.subjectResearch Article
dc.subjectBiochemistry and Chemical Biology
dc.subjectMicrobiology and Infectious Disease
dc.subjectTrypanosoma brucei
dc.subjectaquaporin
dc.subjectdrug transport
dc.subjectpentamidine
dc.subjectdrug resistance
dc.subjectmelarsoprol
dc.subjectOther
dc.titlePositively selected modifications in the pore of TbAQP2 allow pentamidine to enter Trypanosoma brucei
dc.typeArticle
dc.date.updated2020-09-05T05:11:46Z
prism.publicationNameeLife
prism.volume9
dc.identifier.doi10.17863/CAM.57053
dcterms.dateAccepted2020-08-06
rioxxterms.versionofrecord10.7554/elife.56416
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
datacite.contributor.supervisoreditor: Clayton, Christine
datacite.contributor.supervisorsenior_editor: Soldati-Favre, Dominique
dc.contributor.orcidCampagnaro, Gustavo Daniel [0000-0001-6542-0485]
dc.contributor.orcidHulpia, Fabian [0000-0002-7470-3484]
dc.contributor.orcidEze, Anthonius A [0000-0002-4821-1689]
dc.contributor.orcidCarrington, Mark [0000-0002-6435-7266]
dc.contributor.orcidDe Koning, Harry P [0000-0002-9963-1827]
dc.identifier.eissn2050-084X
pubs.funder-project-idMedical Research Council (G0701258)
pubs.funder-project-idNational Institutes of Health (GM111749)
pubs.funder-project-idMedical Research Council (MR/R015791/1)
pubs.funder-project-idScience Without Borders, Brazil (206385/2014-5)
pubs.funder-project-idWellcome (204697/Z/16/Z)


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Attribution 4.0 International (CC BY 4.0)
Except where otherwise noted, this item's licence is described as Attribution 4.0 International (CC BY 4.0)