Structure of the Plasmodium falciparum M17 aminopeptidase and significance for the design of drugs targeting the neutral exopeptidases.

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dc.contributor.author McGowan, S
dc.contributor.author Oellig, CA
dc.contributor.author Birru, WA
dc.contributor.author Caradoc-Davies, TT
dc.contributor.author Stack, CM
dc.contributor.author Lowther, J
dc.contributor.author Skinner-Adams, T
dc.contributor.author Mucha, A
dc.contributor.author Kafarski, P
dc.contributor.author Grembecka, J
dc.contributor.author Trenholme, KR
dc.contributor.author Buckle, AM
dc.contributor.author Gardiner, DL
dc.contributor.author Dalton, JP
dc.contributor.author Whisstock, JC
dc.date.accessioned 2012-02-02T05:06:33Z
dc.date.issued 2010-02
dc.identifier.citation Proceedings of the National Academy of Sciences of the United States of America, 2010, 107 (6), pp. 2449 - 2454
dc.identifier.issn 0027-8424
dc.identifier.other C1 en_US
dc.identifier.uri http://hdl.handle.net/10453/14605
dc.description.abstract Current therapeutics and prophylactics for malaria are under severe challenge as a result of the rapid emergence of drug-resistant parasites. The human malaria parasite Plasmodium falciparum expresses two neutral aminopeptidases, PfA-M1 and PfA-M17, which function in regulating the intracellular pool of amino acids required for growth and development inside the red blood cell. These enzymes are essential for parasite viability and are validated therapeutic targets. We previously reported the X-ray crystal structure of the monomeric PfA-M1 and proposed a mechanism for substrate entry and free amino acid release from the active site. Here, we present the X-ray crystal structure of the hexameric leucine aminopeptidase, PfA-M17, alone and in complex with two inhibitors with antimalarial activity. The six active sites of the PfA-M17 hexamer are arranged in a disc-like fashion so that they are orientated inwards to form a central catalytic cavity; flexible loops that sit at each of the six entrances to the catalytic cavern function to regulate substrate access. In stark contrast to PfA-M1, PfA-M17 has a narrow and hydrophobic primary specificity pocket which accounts for its highly restricted substrate specificity. We also explicate the essential roles for the metal-binding centers in these enzymes (two in PfA-M17 and one in PfA-M1) in both substrate and drug binding. Our detailed understanding of the PfA-M1 and PfA-M17 active sites now permits a rational approach in the development of a unique class of two-target and/or combination antimalarial therapy.
dc.format Print-Electronic
dc.language eng
dc.relation.isbasedon 10.1073/pnas.0911813107
dc.title Structure of the Plasmodium falciparum M17 aminopeptidase and significance for the design of drugs targeting the neutral exopeptidases.
dc.type Journal Article
dc.parent Proceedings of the National Academy of Sciences of the United States of America
dc.journal.volume 6
dc.journal.volume 107
dc.journal.number 6 en_US
dc.publocation Washington, USA en_US
dc.identifier.startpage 2449 en_US
dc.identifier.endpage 2454 en_US
dc.cauo.name SCI.Institute for Biotechnology of Infectious Diseases en_US
dc.conference Verified OK en_US
dc.for 0301 Analytical Chemistry
dc.personcode 995262
dc.personcode 030896
dc.personcode 996591
dc.percentage 100 en_US
dc.classification.name Analytical Chemistry 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 ISI:000274408100019 en_US
dc.location.activity ISI:000253759600025
dc.description.keywords Plasmodium falciparum
dc.description.keywords Plasmodium falciparum
dc.description.keywords Metals
dc.description.keywords Metals
dc.description.keywords Aminopeptidases
dc.description.keywords Aminopeptidases
dc.description.keywords Protozoan Proteins
dc.description.keywords Protozoan Proteins
dc.description.keywords Crystallography, X-Ray
dc.description.keywords Crystallography, X-Ray
dc.description.keywords Catalytic Domain
dc.description.keywords Catalytic Domain
dc.description.keywords Protein Structure, Quaternary
dc.description.keywords Protein Structure, Quaternary
dc.description.keywords Protein Structure, Tertiary
dc.description.keywords Protein Structure, Tertiary
dc.description.keywords Protein Binding
dc.description.keywords Protein Binding
dc.description.keywords Substrate Specificity
dc.description.keywords Substrate Specificity
dc.description.keywords Drug Design
dc.description.keywords Drug Design
dc.description.keywords Antimalarials
dc.description.keywords Antimalarials
dc.description.keywords Catalysis
dc.description.keywords Catalysis
dc.description.keywords Protein Multimerization
dc.description.keywords Protein Multimerization
dc.description.keywords Hydrophobic and Hydrophilic Interactions
dc.description.keywords Hydrophobic and Hydrophilic Interactions
dc.description.keywords Models, Molecular
dc.description.keywords Models, Molecular
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
utslib.copyright.date 2015-04-15 12:17:09.805752+10
pubs.consider-herdc true
pubs.consider-herdc true
utslib.collection.history Closed (ID: 3)


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