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

Autor:	Alghamdi AH; Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom., Munday JC; Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom., Campagnaro GD; Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom., Gurvic D; Computational Biology Centre for Translational and Interdisciplinary Research, University of Dundee, Dundee, United Kingdom., Svensson F; IOTA Pharmaceuticals Ltd, St Johns Innovation Centre, Cambridge, United Kingdom., Okpara CE; Department of Chemistry, University of Liverpool, Liverpool, United Kingdom., Kumar A; Chemistry Department, Georgia State University, Atlanta, United States., Quintana J; School of Life Sciences, University of Dundee, Dundee, United Kingdom., Martin Abril ME; Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom., Milić P; Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom., Watson L; Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom., Paape D; Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom., Settimo L; Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom., Dimitriou A; Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom., Wielinska J; Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom., Smart G; Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom., Anderson LF; Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom., Woodley CM; Department of Chemistry, University of Liverpool, Liverpool, United Kingdom., Kelly SPY; Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom., Ibrahim HM; Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom., Hulpia F; Laboratory for Medicinal Chemistry, University of Ghent, Ghent, Belgium., Al-Salabi MI; Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom., Eze AA; Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom., Sprenger T; Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom., Teka IA; Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom., Gudin S; Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom., Weyand S; Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom., Field M; School of Life Sciences, University of Dundee, Dundee, United Kingdom.; Institute of Parasitology, Biology Centre, Czech Academy of Sciences, Ceske Budejovice, Czech Republic., Dardonville C; Instituto de Química Médica - CSIC, Madrid, Spain., Tidwell RR; Department of Pathology and Lab Medicine, University of North Carolina at Chapel Hill, Chapel Hill, United States., Carrington M; Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom., O'Neill P; Department of Chemistry, University of Liverpool, Liverpool, United Kingdom., Boykin DW; Chemistry Department, Georgia State University, Atlanta, United States., Zachariae U; Computational Biology Centre for Translational and Interdisciplinary Research, University of Dundee, Dundee, United Kingdom., De Koning HP; Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2020 Aug 11; Vol. 9. Date of Electronic Publication: 2020 Aug 11.
DOI:	10.7554/eLife.56416
Abstrakt:	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. Competing Interests: AA, JM, GC, DG, CO, AK, JQ, MM, PM, LW, DP, LS, AD, JW, GS, LA, CW, SK, HI, FH, MA, AE, IT, SG, MF, CD, RT, MC, PO, DB, UZ, HD No competing interests declared, FS Was an employee of IOTA Pharmaceuticals Ltd at the time (© 2020, Alghamdi et al.)
Databáze:	MEDLINE
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