title: Structural basis for plasmepsin V inhibition that blocks export of malaria proteins to human erythrocytes.
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.affiliation: 1] Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. [2] Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Anthony N
authors.initials: AN
authors.lastname: Hodder
authors.affiliation: 1] Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. [2] Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Brad E
authors.initials: BE
authors.lastname: Sleebs
authors.affiliation: 1] Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. [2] Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Czabotar
authors.affiliation: 1] Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. [2] Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Michelle
authors.initials: M
authors.lastname: Gazdik
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
authors.forename: Yibin
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: O'Neill
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
authors.forename: Sash
authors.initials: S
authors.lastname: Lopaticki
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
authors.forename: Thomas
authors.initials: T
authors.lastname: Nebl
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
authors.forename: Tony
authors.initials: T
authors.lastname: Triglia
authors.affiliation: La Trobe Institute for Molecular Science, La Trobe University, Victoria, Australia.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Smith
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
authors.forename: Kym
authors.initials: K
authors.lastname: Lowes
authors.affiliation: 1] Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. [2] Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Justin A
authors.initials: JA
authors.lastname: Boddey
authors.affiliation: 1] Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. [2] Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Alan F
authors.initials: AF
authors.lastname: Cowman
mesh_terms: D020816:Amino Acid Motifs / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D002219:Carbamates / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002460:Cell Line; D018360:Crystallography, X-Ray; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D010963:Plasmodium falciparum / Q000201:enzymology / Q000235:genetics; D010966:Plasmodium vivax / Q000201:enzymology / Q000235:genetics; D011480:Protease Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000187:drug effects; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity; D020349:Surface Plasmon Resonance
chemical_list: D002219:Carbamates; C411566:EMP3 protein, Plasmodium falciparum; D008565:Membrane Proteins; D009842:Oligopeptides; D010455:Peptides; D011480:Protease Inhibitors; D015800:Protozoan Proteins; C000602894:WEHI-842; D049452:Green Fluorescent Proteins; D016282:Aspartic Acid Endopeptidases; C089643:plasmepsin