3EBI

Structure of the M1 Alanylaminopeptidase from malaria complexed with the phosphinate dipeptide analog

3EBI の概要

• エントリーDOI: 10.2210/pdb3ebi/pdb
• 関連するPDBエントリー: 3EBG 3EBH
• 分子名称: M1 family aminopeptidase, ZINC ION, (2S)-3-[(R)-[(1S)-1-amino-3-phenylpropyl](hydroxy)phosphoryl]-2-benzylpropanoic acid, ... (6 entities in total)
• 機能のキーワード: hydrolase, aminopeptidase, metal-binding, metalloprotease, protease, hydrolase inhibitor
• 由来する生物種: Plasmodium falciparum
• 細胞内の位置: Cytoplasm: O96935
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 104745.19

構造登録者

McGowan, S.,Porter, C.J.,Buckle, A.M.,Whisstock, J.C. (登録日: 2008-08-27, 公開日: 2009-01-27, 最終更新日: 2024-02-21)

主引用文献

McGowan, S.,Porter, C.J.,Lowther, J.,Stack, C.M.,Golding, S.J.,Skinner-Adams, T.S.,Trenholme, K.R.,Teuscher, F.,Donnelly, S.M.,Grembecka, J.,Mucha, A.,Kafarski, P.,Degori, R.,Buckle, A.M.,Gardiner, D.L.,Whisstock, J.C.,Dalton, J.P.
Structural basis for the inhibition of the essential Plasmodium falciparum M1 neutral aminopeptidase
Proc.Natl.Acad.Sci.USA, 106:2537-2542, 2009

PubMed 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.

PubMed: 19196988
DOI: 10.1073/pnas.0807398106

実験手法

X-RAY DIFFRACTION (2 Å)