5CS2

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

Summary for 5CS2

• Entry DOI: 10.2210/pdb5cs2/pdb
• Descriptor: Histidine triad protein, Cyclomarin A, CHLORIDE ION, ... (4 entities in total)
• Functional Keywords: cyclomarin a, diadenosine triphosphate hydrolase, anti-plasmodial activity, malaria, plasmodium falciparum, hydrolase
• Biological source: Plasmodium falciparum 3D7; More
• Total number of polymer chains: 2
• Total formula weight: 24744.58

Authors

Ostermann, N.,Schmitt, E.,Gerhartz, B.,Hinniger, A.,Delmas, C. (deposition date: 2015-07-23, release date: 2015-10-28, Last modification date: 2024-11-20)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.65 Å)