5CS2

Crystal structure of Plasmodium falciparum diadenosine triphosphate hydrolase in complex with Cyclomarin A

5CS2 の概要

• エントリーDOI: 10.2210/pdb5cs2/pdb
• 分子名称: Histidine triad protein, Cyclomarin A, CHLORIDE ION, ... (4 entities in total)
• 機能のキーワード: cyclomarin a, diadenosine triphosphate hydrolase, anti-plasmodial activity, malaria, plasmodium falciparum, hydrolase
• 由来する生物種: Plasmodium falciparum 3D7; 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 24744.58

構造登録者

Ostermann, N.,Schmitt, E.,Gerhartz, B.,Hinniger, A.,Delmas, C. (登録日: 2015-07-23, 公開日: 2015-10-28, 最終更新日: 2024-11-20)

主引用文献

Burstner, N.,Roggo, S.,Ostermann, N.,Blank, J.,Delmas, C.,Freuler, F.,Gerhartz, B.,Hinniger, A.,Hoepfner, D.,Liechty, B.,Mihalic, M.,Murphy, J.,Pistorius, D.,Rottmann, M.,Thomas, J.R.,Schirle, M.,Schmitt, E.K.
Gift from Nature: Cyclomarin A Kills Mycobacteria and Malaria Parasites by Distinct Modes of Action.
Chembiochem, 16:2433-2436, 2015

PubMed Abstract: Malaria continues to be one of the most devastating human diseases despite many efforts to limit its spread by prevention of infection or by pharmaceutical treatment of patients. We have conducted a screen for antiplasmodial compounds by using a natural product library. Here we report on cyclomarin A as a potent growth inhibitor of Plasmodium falciparum and the identification of its molecular target, diadenosine triphosphate hydrolase (PfAp3Aase), by chemical proteomics. Using a biochemical assay, we could show that cyclomarin A is a specific inhibitor of the plasmodial enzyme but not of the closest human homologue hFHIT. Co-crystallisation experiments demonstrate a unique binding mode of the inhibitor. One molecule of cyclomarin A binds a dimeric PfAp3Aase and prevents the formation of the enzyme⋅substrate complex. These results validate PfAp3Aase as a new drug target for the treatment of malaria. We have previously elucidated the structurally unrelated regulatory subunit ClpC1 of the ClpP protease as the molecular target of cyclomarin A in Mycobacterium tuberculosis. Thus, cyclomarin A is a rare example of a natural product with two distinct and specific modes of action.

PubMed: 26472355
DOI: 10.1002/cbic.201500472

実験手法

X-RAY DIFFRACTION (1.65 Å)