5cs2 | pdb_00005cs2

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

spinqualitylabelsall models 5cs2, resolution 1.65Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5cs2 is a 2 chain structure with sequence from Plasmodium falciparum 3D7 and Streptomyces. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 54C, CL, MLE, WLU, WPA, WVL Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function Q8IL97_PLAF7 Publication Abstract from PubMed 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 enzymesubstrate 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. Gift from Nature: Cyclomarin A Kills Mycobacteria and Malaria Parasites by Distinct Modes of Action.,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 JR, Schirle M, Schmitt EK Chembiochem. 2015 Nov;16(17):2433-6. doi: 10.1002/cbic.201500472. Epub 2015 Oct, 16. PMID:26472355 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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