X-ray crystal structure and specificity of the plasmodium falciparum malaria aminopeptidase PfM18AAP

Sivaraman, Komagal Kannan, Oellig, Christine A., Huynh, Kitmun, Atkinson, Sarah C., Poreba, Marcin, Perugini, Matthew A., Trenholme, Katharine R., Gardiner, Donald L., Salvesen, Guy, Drag, Marcin, Dalton, John P., Whisstock, James C. and McGowan, Sheena (2012) X-ray crystal structure and specificity of the plasmodium falciparum malaria aminopeptidase PfM18AAP. Journal of Molecular Biology, 422 4: 495-507. doi:10.1016/j.jmb.2012.06.006


Author Sivaraman, Komagal Kannan
Oellig, Christine A.
Huynh, Kitmun
Atkinson, Sarah C.
Poreba, Marcin
Perugini, Matthew A.
Trenholme, Katharine R.
Gardiner, Donald L.
Salvesen, Guy
Drag, Marcin
Dalton, John P.
Whisstock, James C.
McGowan, Sheena
Title X-ray crystal structure and specificity of the plasmodium falciparum malaria aminopeptidase PfM18AAP
Journal name Journal of Molecular Biology   Check publisher's open access policy
ISSN 0022-2836
Publication date 2012-09
Sub-type Article (original research)
DOI 10.1016/j.jmb.2012.06.006
Volume 422
Issue 4
Start page 495
End page 507
Total pages 13
Place of publication London, United Kingdom
Publisher Academic Press
Collection year 2013
Language eng
Abstract The malarial aminopeptidases have emerged as promising new drug targets for the development of novel antimalarial drugs. The M18AAP of Plasmodium falciparum malaria is a metallo-aminopeptidase that we show demonstrates a highly restricted specificity for peptides with an N-terminal Glu or Asp residue. Thus, the enzyme may function alongside other aminopeptidases in effecting the complete degradation or turnover of proteins, such as host hemoglobin, which provides a free amino acid pool for the growing parasite. Inhibition of PfM18AAP's function using antisense RNA is detrimental to the intra-erythrocytic malaria parasite and, hence, it has been proposed as a potential novel drug target. We report the X-ray crystal structure of the PfM18AAP aminopeptidase and reveal its complex dodecameric assembly arranged via dimer and trimer units that interact to form a large tetrahedron shape that completely encloses the 12 active sites within a central cavity. The four entry points to the catalytic lumen are each guarded by 12 large flexible loops that could control substrate entry into the catalytic sites. PfM18AAP thus resembles a proteasomal-like machine with multiple active sites able to degrade peptide substrates that enter the central lumen. The Plasmodium enzyme shows significant structural differences around the active site when compared to recently determined structures of its mammalian and human homologs, which provides a platform from which a rational approach to inhibitor design of new malaria-specific drugs can begin.
Keyword Aminopeptidase
Malaria
Protease
Structural biology
Drug design
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Available online: 16 June 2012.

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2013 Collection
School of Medicine Publications
 
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