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

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...

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Autores principales: Alghamdi, Ali H, Munday, Jane C, Campagnaro, Gustavo Daniel, Gurvic, Dominik, Svensson, Fredrik, Okpara, Chinyere E, Kumar, Arvind, Quintana, Juan, Martin Abril, Maria Esther, Milić, Patrik, Watson, Laura, Paape, Daniel, Settimo, Luca, Dimitriou, Anna, Wielinska, Joanna, Smart, Graeme, Anderson, Laura F, Woodley, Christopher M, Kelly, Siu Pui Ying, Ibrahim, Hasan MS, Hulpia, Fabian, Al-Salabi, Mohammed I, Eze, Anthonius A, Sprenger, Teresa, Teka, Ibrahim A, Gudin, Simon, Weyand, Simone, Field, Mark, Dardonville, Christophe, Tidwell, Richard R, Carrington, Mark, O'Neill, Paul, Boykin, David W, Zachariae, Ulrich, De Koning, Harry P
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473772/
https://www.ncbi.nlm.nih.gov/pubmed/32762841
http://dx.doi.org/10.7554/eLife.56416
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author Alghamdi, Ali H
Munday, Jane C
Campagnaro, Gustavo Daniel
Gurvic, Dominik
Svensson, Fredrik
Okpara, Chinyere E
Kumar, Arvind
Quintana, Juan
Martin Abril, Maria Esther
Milić, Patrik
Watson, Laura
Paape, Daniel
Settimo, Luca
Dimitriou, Anna
Wielinska, Joanna
Smart, Graeme
Anderson, Laura F
Woodley, Christopher M
Kelly, Siu Pui Ying
Ibrahim, Hasan MS
Hulpia, Fabian
Al-Salabi, Mohammed I
Eze, Anthonius A
Sprenger, Teresa
Teka, Ibrahim A
Gudin, Simon
Weyand, Simone
Field, Mark
Dardonville, Christophe
Tidwell, Richard R
Carrington, Mark
O'Neill, Paul
Boykin, David W
Zachariae, Ulrich
De Koning, Harry P
author_facet Alghamdi, Ali H
Munday, Jane C
Campagnaro, Gustavo Daniel
Gurvic, Dominik
Svensson, Fredrik
Okpara, Chinyere E
Kumar, Arvind
Quintana, Juan
Martin Abril, Maria Esther
Milić, Patrik
Watson, Laura
Paape, Daniel
Settimo, Luca
Dimitriou, Anna
Wielinska, Joanna
Smart, Graeme
Anderson, Laura F
Woodley, Christopher M
Kelly, Siu Pui Ying
Ibrahim, Hasan MS
Hulpia, Fabian
Al-Salabi, Mohammed I
Eze, Anthonius A
Sprenger, Teresa
Teka, Ibrahim A
Gudin, Simon
Weyand, Simone
Field, Mark
Dardonville, Christophe
Tidwell, Richard R
Carrington, Mark
O'Neill, Paul
Boykin, David W
Zachariae, Ulrich
De Koning, Harry P
author_sort Alghamdi, Ali H
collection PubMed
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.
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spelling pubmed-74737722020-09-08 Positively selected modifications in the pore of TbAQP2 allow pentamidine to enter Trypanosoma brucei Alghamdi, Ali H Munday, Jane C Campagnaro, Gustavo Daniel Gurvic, Dominik Svensson, Fredrik Okpara, Chinyere E Kumar, Arvind Quintana, Juan Martin Abril, Maria Esther Milić, Patrik Watson, Laura Paape, Daniel Settimo, Luca Dimitriou, Anna Wielinska, Joanna Smart, Graeme Anderson, Laura F Woodley, Christopher M Kelly, Siu Pui Ying Ibrahim, Hasan MS Hulpia, Fabian Al-Salabi, Mohammed I Eze, Anthonius A Sprenger, Teresa Teka, Ibrahim A Gudin, Simon Weyand, Simone Field, Mark Dardonville, Christophe Tidwell, Richard R Carrington, Mark O'Neill, Paul Boykin, David W Zachariae, Ulrich De Koning, Harry P eLife Biochemistry and Chemical Biology 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. eLife Sciences Publications, Ltd 2020-08-11 /pmc/articles/PMC7473772/ /pubmed/32762841 http://dx.doi.org/10.7554/eLife.56416 Text en © 2020, Alghamdi et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Biochemistry and Chemical Biology
Alghamdi, Ali H
Munday, Jane C
Campagnaro, Gustavo Daniel
Gurvic, Dominik
Svensson, Fredrik
Okpara, Chinyere E
Kumar, Arvind
Quintana, Juan
Martin Abril, Maria Esther
Milić, Patrik
Watson, Laura
Paape, Daniel
Settimo, Luca
Dimitriou, Anna
Wielinska, Joanna
Smart, Graeme
Anderson, Laura F
Woodley, Christopher M
Kelly, Siu Pui Ying
Ibrahim, Hasan MS
Hulpia, Fabian
Al-Salabi, Mohammed I
Eze, Anthonius A
Sprenger, Teresa
Teka, Ibrahim A
Gudin, Simon
Weyand, Simone
Field, Mark
Dardonville, Christophe
Tidwell, Richard R
Carrington, Mark
O'Neill, Paul
Boykin, David W
Zachariae, Ulrich
De Koning, Harry P
Positively selected modifications in the pore of TbAQP2 allow pentamidine to enter Trypanosoma brucei
title Positively selected modifications in the pore of TbAQP2 allow pentamidine to enter Trypanosoma brucei
title_full Positively selected modifications in the pore of TbAQP2 allow pentamidine to enter Trypanosoma brucei
title_fullStr Positively selected modifications in the pore of TbAQP2 allow pentamidine to enter Trypanosoma brucei
title_full_unstemmed Positively selected modifications in the pore of TbAQP2 allow pentamidine to enter Trypanosoma brucei
title_short Positively selected modifications in the pore of TbAQP2 allow pentamidine to enter Trypanosoma brucei
title_sort positively selected modifications in the pore of tbaqp2 allow pentamidine to enter trypanosoma brucei
topic Biochemistry and Chemical Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473772/
https://www.ncbi.nlm.nih.gov/pubmed/32762841
http://dx.doi.org/10.7554/eLife.56416
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