Structural basis for plasmepsin V inhibition that blocks export of malaria proteins to human erythrocytes
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
NHMRC Grants
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Creation Date: 2015-09-01 03:55:19
Last Modified: 2015-09-02 03:02:05
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