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

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dc.contributor.author Sivaraman, KK
dc.contributor.author Oellig, CA
dc.contributor.author Huynh, K
dc.contributor.author Atkinson, SC
dc.contributor.author Poreba, M
dc.contributor.author Perugini, MA
dc.contributor.author Trenholme, KR
dc.contributor.author Gardiner, DL
dc.contributor.author Salvesen, G
dc.contributor.author Drag, M
dc.contributor.author Dalton, JP
dc.contributor.author Whisstock, JC
dc.contributor.author McGowan, S
dc.date.accessioned 2014-04-03T01:22:51Z
dc.date.issued 2012-09
dc.identifier.citation Journal of molecular biology, 2012, 422 (4), pp. 495 - 507
dc.identifier.issn 0022-2836
dc.identifier.other C1 en_US
dc.identifier.uri http://hdl.handle.net/10453/22814
dc.description.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.
dc.format Print-Electronic
dc.language eng
dc.relation.isbasedon 10.1016/j.jmb.2012.06.006
dc.title X-ray crystal structure and specificity of the Plasmodium falciparum malaria aminopeptidase PfM18AAP.
dc.type Journal Article
dc.parent Journal of molecular biology
dc.journal.volume 4
dc.journal.volume 422
dc.journal.number 4 en_US
dc.publocation London en_US
dc.identifier.startpage 495 en_US
dc.identifier.endpage 507 en_US
dc.cauo.name SCI.Faculty of Science en_US
dc.conference Verified OK en_US
dc.for 0601 Biochemistry and Cell Biology
dc.personcode 030896
dc.percentage 100 en_US
dc.classification.name Biochemistry and Cell Biology en_US
dc.classification.type FOR-08 en_US
dc.edition en_US
dc.custom en_US
dc.date.activity en_US
dc.location.activity en_US
dc.description.keywords Animals
dc.description.keywords Humans
dc.description.keywords Erythrocytes
dc.description.keywords Plasmodium falciparum
dc.description.keywords Malaria, Falciparum
dc.description.keywords Peptides
dc.description.keywords Aminopeptidases
dc.description.keywords Amino Acids
dc.description.keywords Protozoan Proteins
dc.description.keywords Recombinant Proteins
dc.description.keywords Crystallography, X-Ray
dc.description.keywords Catalytic Domain
dc.description.keywords Substrate Specificity
dc.description.keywords Proteolysis
pubs.embargo.period Not known
pubs.organisational-group /University of Technology Sydney
pubs.organisational-group /University of Technology Sydney/Faculty of Science
utslib.copyright.status Closed Access
utslib.copyright.date 2015-04-15 12:17:09.805752+10
pubs.consider-herdc true
utslib.collection.history Closed (ID: 3)


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