Structural basis for plasmepsin v inhibition that blocks export of malaria proteins to human erythrocytes

Anthony N Hodder, Brad E Sleebs, Peter E. Czabotar, Michelle Gazdik, Yibin Xu, Matthew T. O'Neill, Sash Lopaticki, Thomas Nebl, Tony Triglia, Brian J. Smith, Kym Lowes, Justin A Boddey, Alan Frederick Cowman

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54 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)590-596
Number of pages7
JournalNature Structural & Molecular Biology
Issue number8
Publication statusPublished - 7 Aug 2015
Externally publishedYes

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