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

McGowan, Sheena, Porter, Corrine J., Lowther, Jonathan, Stack, Colin M., Golding, Sarah J., Skinner-Adams, Tina S., Trenholme, Katharine R., Teuscher, Franka, Donnelly, Sheila M., Grembecka, Jolanta, Mucha, Artur, Kafarski, Pawel, DeGori, Ross, Buckle, Ashley M., Gardiner, Donald L., Whisstock, James C. and Dalton, John P. (2009) Structural basis for the inhibition of the essential Plasmodium falciparum M1 neutral aminopeptidase. Proceedings of the National Academy of Sciences of USA, 106 8: 2537-2542. doi:10.1073/pnas.0807398106

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Author McGowan, Sheena
Porter, Corrine J.
Lowther, Jonathan
Stack, Colin M.
Golding, Sarah J.
Skinner-Adams, Tina S.
Trenholme, Katharine R.
Teuscher, Franka
Donnelly, Sheila M.
Grembecka, Jolanta
Mucha, Artur
Kafarski, Pawel
DeGori, Ross
Buckle, Ashley M.
Gardiner, Donald L.
Whisstock, James C.
Dalton, John P.
Title Structural basis for the inhibition of the essential Plasmodium falciparum M1 neutral aminopeptidase
Formatted title
Structural basis for the inhibition of the essential Plasmodium falciparum M1 neutral aminopeptidase
Journal name Proceedings of the National Academy of Sciences of USA   Check publisher's open access policy
ISSN 0027-8424
1091-6490
Publication date 2009-02-24
Sub-type Article (original research)
DOI 10.1073/pnas.0807398106
Open Access Status File (Publisher version)
Volume 106
Issue 8
Start page 2537
End page 2542
Total pages 6
Place of publication Washington, DC, United States
Publisher National Academy of Sciences
Language eng
Formatted 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[CH2]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.
Keyword Drug design
Malaria
Structural biology
Protease
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
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Created: Tue, 15 Nov 2011, 11:37:35 EST by Miss Kristy Reid on behalf of School of Medicine