Structural basis for plasmep sin V inhibition that blocks export of malaria proteins to human erythrocytes Academic Article uri icon

abstract

  • Plasmepsin V, an essential aspartyl protease of malaria parasites, has a key role in the export of effector proteins to parasite-infected erythrocytes. Consequently, it is an important drug target for the two most virulent malaria parasites of humans, Plasmodium falciparum and Plasmodium vivax. We developed a potent inhibitor of plasmepsin V, called WEHI-842, which directly mimics the Plasmodium export element (PEXEL). WEHI-842 inhibits recombinant plasmepsin V with a half-maximal inhibitory concentration of 0.2 nM, efficiently blocks protein export and inhibits parasite growth. We obtained the structure of P. vivax plasmepsin V in complex with WEHI-842 to 2.4-Å resolution, which provides an explanation for the strict requirements for substrate and inhibitor binding. The structure characterizes both a plant-like fold and a malaria-specific helix-turn-helix motif that are likely to be important in cleavage of effector substrates for export.

authors

  • Hodder, AN
  • Sleebs, BE
  • Czabotar, PE
  • Gazdik, M
  • Xu, Y
  • O'Neill, MT
  • Lopaticki, S
  • Nebl, T
  • Triglia, T
  • Smith, BJ
  • Lowes, K
  • Boddey, JA
  • Cowman, AF

publication date

  • 2015

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