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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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2020
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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. |
format | Online Article Text |
id | pubmed-7473772 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
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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