Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 22, Issue 8, Pages 590-596Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.3061
Keywords
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Funding
- Victorian State Government Operational Infrastructure Support
- Australian Government National Health and Medical Research Council (NHMRC) Independent Research Institute Infrastructure Support Scheme
- Australian Cancer Research Foundation
- NHMRC [1057960, 637406, 1010326]
- University of Melbourne
- National Health and Medical Research Council of Australia [1057960] Funding Source: NHMRC
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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-angstrom 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.
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