Structural basis for the inhibition of the essential Plasmodium falciparum M1 neutral aminopeptidase

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dc.contributor.author McGowan, S
dc.contributor.author Porter, CJ
dc.contributor.author Lowther, J
dc.contributor.author Stack, CM
dc.contributor.author Golding, SJ
dc.contributor.author Skinner-Adams, TS
dc.contributor.author Trenholme, KR
dc.contributor.author Teuscher, F
dc.contributor.author Donnelly, SM
dc.contributor.author Grembecka, J
dc.contributor.author Mucha, A
dc.contributor.author Kafarski, P
dc.contributor.author Degori, R
dc.contributor.author Buckle, AM
dc.contributor.author Gardiner, DL
dc.contributor.author Whisstock, JC
dc.contributor.author Dalton, JP
dc.date.accessioned 2010-07-13T08:48:24Z
dc.date.issued 2009-02-24
dc.identifier.citation Proceedings of the National Academy of Sciences of the United States of America, 2009, 106 (8), pp. 2537 - 2542
dc.identifier.issn 0027-8424
dc.identifier.other C1 en_US
dc.identifier.uri http://hdl.handle.net/10453/12540
dc.description.abstract Plasmodium falciparum parasites are responsible for the major global disease malaria, which results in > 2 million deaths each year. With the rise of drug-resistant malarial parasites, novel drug targets and lead compounds are urgently required for the development of new therapeutic strategies. Here, we address this important problem by targeting the malarial neutral aminopeptidases that are involved in the terminal stages of hemoglobin digestion and essential for the provision of amino acids used for parasite growth and development within the erythrocyte. We characterize the structure and substrate specificity of one such aminopeptidase, PfA-M1, a validated drug target. The X-ray crystal structure of PfA-M1 alone and in complex with the generic inhibitor, bestatin, and a phosphinate dipeptide analogue with potent in vitro and in vivo antimalarial activity, hPheP[CH 2]Phe, reveals features within the protease active site that are critical to its function as an aminopeptidase and can be exploited for drug development. These results set the groundwork for the development of antimalarial therapeutics that target the neutral aminopeptidases of the parasite. © 2009 by The National Academy of Sciences of the USA.
dc.language eng
dc.relation.isbasedon 10.1073/pnas.0807398106
dc.title Structural basis for the inhibition of the essential Plasmodium falciparum M1 neutral aminopeptidase
dc.type Journal Article
dc.parent Proceedings of the National Academy of Sciences of the United States of America
dc.journal.volume 8
dc.journal.volume 106
dc.journal.number 8 en_US
dc.publocation USA en_US
dc.identifier.startpage 2537 en_US
dc.identifier.endpage 2542 en_US
dc.cauo.name SCI.Faculty of Science en_US
dc.conference Verified OK en_US
dc.for 0605 Microbiology
dc.personcode 995262
dc.personcode 995261
dc.personcode 030896
dc.personcode 996591
dc.percentage 100 en_US
dc.classification.name Microbiology 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 Drug design
dc.description.keywords Malaria
dc.description.keywords Protease
dc.description.keywords Structural biology
pubs.embargo.period Not known
pubs.organisational-group /University of Technology Sydney
pubs.organisational-group /University of Technology Sydney/Faculty of Science
pubs.organisational-group /University of Technology Sydney/Strength - i3
pubs.organisational-group /University of Technology Sydney/Strength - i3
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)
utslib.collection.history School of Medical and Molecular Sciences (ID: 341)


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