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

Nature Structural and Molecular Biology

Volumn 22, Issue 8, 2015, Pages 590-596

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

^a WALTER AND ELIZA HALL INSTITUTE OF MEDICAL RESEARCH   (Australia)

^b UNIVERSITY OF MELBOURNE   (Australia)

^c LA TROBE UNIVERSITY   (Australia)

Author keywords

[No Author keywords available]

Indexed keywords

ASPARTIC PROTEINASE; PLASMEPSIN INHIBITOR; PLASMEPSIN V; UNCLASSIFIED DRUG; WEHI 842; CARBAMIC ACID DERIVATIVE; EMP3 PROTEIN, PLASMODIUM FALCIPARUM; GREEN FLUORESCENT PROTEIN; MEMBRANE PROTEIN; OLIGOPEPTIDE; PEPTIDE; PLASMEPSIN; PROTEIN BINDING; PROTEINASE INHIBITOR; PROTOZOAL PROTEIN; WEHI-842;

ARTICLE; COMPLEX FORMATION; CONTROLLED STUDY; DRUG PROTEIN BINDING; ENZYME BINDING; ENZYME INHIBITION; ENZYME SUBSTRATE COMPLEX; ERYTHROCYTE; GROWTH INHIBITION; HUMAN; HUMAN CELL; IC50; NONHUMAN; PLASMODIUM; PLASMODIUM VIVAX; PRIORITY JOURNAL; PROTEIN CLEAVAGE; X RAY CRYSTALLOGRAPHY; AMINO ACID SEQUENCE; ANIMAL; ANTAGONISTS AND INHIBITORS; CELL LINE; CHEMICAL STRUCTURE; CHEMISTRY; DRUG EFFECTS; ENZYME SPECIFICITY; ENZYMOLOGY; GENETICS; IMMUNOBLOTTING; METABOLISM; MOLECULAR GENETICS; PLASMODIUM FALCIPARUM; PROTEIN MOTIF; PROTEIN TERTIARY STRUCTURE; PROTEIN TRANSPORT; SEQUENCE HOMOLOGY; SURFACE PLASMON RESONANCE;

PLASMODIUM FALCIPARUM; PLASMODIUM VIVAX;

AMINO ACID MOTIFS; AMINO ACID SEQUENCE; ANIMALS; ASPARTIC ACID ENDOPEPTIDASES; CARBAMATES; CELL LINE; CRYSTALLOGRAPHY, X-RAY; ERYTHROCYTES; GREEN FLUORESCENT PROTEINS; HUMANS; IMMUNOBLOTTING; MEMBRANE PROTEINS; MODELS, MOLECULAR; MOLECULAR SEQUENCE DATA; MOLECULAR STRUCTURE; OLIGOPEPTIDES; PEPTIDES; PLASMODIUM FALCIPARUM; PLASMODIUM VIVAX; PROTEASE INHIBITORS; PROTEIN BINDING; PROTEIN STRUCTURE, TERTIARY; PROTEIN TRANSPORT; PROTOZOAN PROTEINS; SEQUENCE HOMOLOGY, AMINO ACID; SUBSTRATE SPECIFICITY; SURFACE PLASMON RESONANCE;

EID: 84938742234     PISSN: 15459993     EISSN: 15459985     Source Type: Journal    
DOI: 10.1038/nsmb.3061     Document Type: Article

References (38)

1. Boddey, J. A. et al. An aspartyl protease directs malaria effector proteins to the host cell. Nature 463, 627-631 (2010).
2. Russo, I. et al. Plasmepsin V licenses Plasmodium proteins for export into the host erythrocyte. Nature 463, 632-636 (2010).
3. Marti, M., Good, R. T., Rug, M., Knuepfer, E. & Cowman, A. F. Targeting malaria virulence and remodeling proteins to the host erythrocyte. Science 306, 1930-1933 (2004).
4. Hiller, N. L. et al. A host-targeting signal in virulence proteins reveals a secretome in malarial infection. Science 306, 1934-1937 (2004).
5. Boddey, J. A. & Cowman, A. F. Plasmodium nesting: remaking the erythrocyte from the inside out. Annu. Rev. Microbiol. 67, 243-269 (2013).
6. Sleebs, B. E. et al. Inhibition of Plasmepsin V activity demonstrates its essential role in protein export, PfEMP1 display, and survival of malaria parasites. PLoS Biol. 12, e1001897 (2014).
7. Chang, H. H. et al. N-terminal processing of proteins exported by malaria parasites. Mol. Biochem. Parasitol. 160, 107-115 (2008).
8. Boddey, J. A., Moritz, R. L., Simpson, R. J. & Cowman, A. F. Role of the Plasmodium export element in trafficking parasite proteins to the infected erythrocyte. Traffic 10, 285-299 (2009).
9. Sargeant, T. J. et al. Lineage-specific expansion of proteins exported to erythrocytes in malaria parasites. Genome Biol. 7, R12 (2006).
10. Elsworth, B. et al. PTEX is an essential nexus for protein export in malaria parasites. Nature 511, 587-591 (2014).
11. Beck, J. R., Muralidharan, V., Oksman, A. & Goldberg, D. E. PTEX component HSP101 mediates export of diverse malaria effectors into host erythrocytes. Nature 511, 592-595 (2014).
12. Klemba, M. & Goldberg, D. E. Characterization of plasmepsin V, a membrane-bound aspartic protease homolog in the endoplasmic reticulum of Plasmodium falciparum. Mol. Biochem. Parasitol. 143, 183-191 (2005).
13. Gazdik, M. et al. The effect of N-methylation on transition state mimetic inhibitors of the Plasmodium protease, plasmepsin V. Med. Chem. Commun. 6, 437-443 (2015).
14. Masic, L. P. Arginine mimetic structures in biologically active antagonists and inhibitors. Curr. Med. Chem. 13, 3627-3648 (2006).
15. Peterlin-Mašic, L. & Kikelj, D. Arginine mimetics. Tetrahedron 57, 7073-7105 (2001).
16. Sleebs, B. E. et al. Transition state mimetics of the Plasmodium export element are potent inhibitors of Plasmepsin V from P. falciparum and P. vivax. J. Med. Chem. 57, 7644-7662 (2014).
17. Kay, J., Meijer, H. J., ten Have, A. & van Kan, J. A. The aspartic proteinase family of three Phytophthora species. BMC Genomics 12, 254 (2011).
18. Meyers, M. J. & Goldberg, D. E. Recent advances in plasmepsin medicinal chemistry and implications for future antimalarial drug discovery efforts. Curr. Top. Med. Chem. 12, 445-455 (2012).
19. Athauda, S. B. et al. Enzymic and structural characterization of nepenthesin, a unique member of a novel subfamily of aspartic proteinases. Biochem. J. 381, 295-306 (2004).
20. Haque, T. S. et al. Potent, low-molecular-weight non-peptide inhibitors of malarial aspartyl protease plasmepsin II. J. Med. Chem. 42, 1428-1440 (1999).
21. Ghosh, A. K. et al. Structure-based design: Potent inhibitors of human brain memapsin 2 (-secretase). J. Med. Chem. 44, 2865-2868 (2001).
22. Johansson, P.-O. et al. Design and synthesis of potent inhibitors of plasmepsin I and II: X-ray crystal structure of inhibitor in complex with plasmepsin II. J. Med. Chem. 48, 4400-4409 (2005).
23. Boddey, J. A. et al. Role of Plasmepsin V in export of diverse protein families from the Plasmodium falciparum exportome. Traffic 14, 532-550 (2013).
24. James, M. N. & Sielecki, A. R. Structure and refinement of penicillopepsin at 1. 8 A resolution. J. Mol. Biol. 163, 299-361 (1983).
25. Meanwell, N. A. Synopsis of some recent tactical application of bioisosteres in drug design. J. Med. Chem. 54, 2529-2591 (2011).
26. Schulze, J. et al. The Plasmodium falciparum exportome contains non-canonical PEXEL/HT proteins. Mol. Microbiol. doi:10. 1111/mmi. 13024 (9 May 2015).
27. Shea, M. et al. A family of aspartic proteases and a novel, dynamic and cell-cycle-dependent protease localization in the secretory pathway of Toxoplasma gondii. Traffic 8, 1018-1034 (2007).
28. Xiao, H. et al. The zymogen of plasmepsin V from Plasmodium falciparum is enzymatically active. Mol. Biochem. Parasitol. 197, 56-63 (2014).
29. Baum, J. et al. A conserved molecular motor drives cell invasion and gliding motility across malaria life cycle stages and other apicomplexan parasites. J. Biol. Chem. 281, 5197-5208 (2006).
30. Bianco, A. E. et al. A repetitive antigen of Plasmodium falciparum that is homologous to heat shock protein 70 of Drosophila melanogaster. Proc. Natl. Acad. Sci. USA 83, 8713-8717 (1986).
31. Kabsch, W. XDS. Acta Crystallogr. D Biol. Crystallogr. 66, 125-132 (2010).
32. Evans, P. R. An introduction to data reduction: space-group determination, scaling and intensity statistics. Acta Crystallogr. D Biol. Crystallogr. 67, 282-292 (2011).
33. Evans, P. R. & Murshudov, G. N. How good are my data and what is the resolution? Acta Crystallogr. D Biol. Crystallogr. 69, 1204-1214 (2013).
34. McCoy, A. J. et al. Phaser crystallographic software. J. Appl. Crystallogr. 40, 658-674 (2007).
35. Bunkóczi, G. & Read, R. J. Improvement of molecular-replacement models with Sculptor. Acta Crystallogr. D Biol. Crystallogr. 67, 303-312 (2011).
36. Ostermann, N., Gerhartz, B., Worpenberg, S., Trappe, J. & Eder, J. Crystal structure of an activation intermediate of cathepsin E. J. Mol. Biol. 342, 889-899 (2004).
37. Emsley, P. & Cowtan, K. Coot: model-building tools for molecular graphics. Acta Crystallogr. D Biol. Crystallogr. 60, 2126-2132 (2004).
38. Adams, P. D. et al. PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr. D Biol. Crystallogr. 66, 213-221 (2010).