Structural basis for plasmepsin V inhibition that blocks export of malaria proteins to human erythrocytes
- 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 Year 2015-08, Volume 22, Issue #8, Page 590-6
- Journal Title
- Nat Struct Mol Biol
- Publication Type
- Journal Article
- 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-A 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.
- WEHI Research Division(s)
- Infection And Immunity; Chemical Biology; Structural Biology; Systems Biology And Personalised Medicine
- PubMed ID
- Publisher's Version
- Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2015-09-01 03:55:19Last Modified: 2015-09-02 03:02:05