4jbv

Calcium-Dependent Protein Kinase 1 from Toxoplasma gondii (TgCDPK1) in complex with inhibitor UW1268

spinqualitylabelsall models 4jbv, resolution 1.95Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4jbv is a 1 chain structure with sequence from Toxoplasma gondii. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: V68 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function Q9BJF5_TOXGO Publication Abstract from PubMed Malaria remains a major health concern for a large percentage of the world's population. While great strides have been made in reducing mortality due to malaria, new strategies and therapies are still needed. Therapies that are capable of blocking the transmission of Plasmodium parasites are particularly attractive, but only primaquine accomplishes this, and toxicity issues hamper its widespread use. In this study, we describe a series of pyrazolopyrimidine- and imidazopyrazine-based compounds that are potent inhibitors of PfCDPK4, which is a calcium-activated Plasmodium protein kinase that is essential for exflagellation of male gametocytes. Thus, PfCDPK4 is essential for the sexual development of Plasmodium parasites and their ability to infect mosquitoes. We demonstrate that two structural features in the ATP-binding site of PfCDPK4 can be exploited in order to obtain potent and selective inhibitors of this enzyme. Furthermore, we demonstrate that pyrazolopyrimidine-based inhibitors that are potent inhibitors of the in vitro activity of PfCDPK4 are also able to block Plasmodium falciparum exflagellation with no observable toxicity to human cells. This medicinal chemistry effort serves as a valuable starting point in the development of safe, transmission-blocking agents for the control of malaria. Development of potent and selective Plasmodium falciparum calcium-dependent protein kinase 4 (PfCDPK4) inhibitors that block the transmission of malaria to mosquitoes.,Vidadala RS, Ojo KK, Johnson SM, Zhang Z, Leonard SE, Mitra A, Choi R, Reid MC, Keyloun KR, Fox AM, Kennedy M, Silver-Brace T, Hume JC, Kappe S, Verlinde CL, Fan E, Merritt EA, Van Voorhis WC, Maly DJ Eur J Med Chem. 2014 Mar 3;74:562-73. doi: 10.1016/j.ejmech.2013.12.048. Epub, 2014 Jan 11. PMID:24531197 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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