1vyq

Novel inhibitors of Plasmodium Falciparum dUTPase provide a platform for anti-malarial drug design

spinqualitylabelsall models 1vyq, resolution 2.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 1vyq is a 3 chain structure with sequence from Plasmodium falciparum 3D7. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.4Å Ligands: DUX Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function Q8II92_PLAF7 Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed Pyrimidine metabolism is a major route for therapeutic intervention against malaria. Here we report inhibition and structural studies on the deoxyuridine nucleotidohydrolase from the malaria parasite Plasmodium falciparum (PfdUTPase). We have identified a series of triphenylmethane derivatives of deoxyuridine with antimalarial activity in vitro which inhibit specifically the Plasmodium dUTPase versus the human enzyme. A 2.4 Angstrom crystal structure of PfdUTPase in complex with one of these inhibitors reveals an atypical trimeric enzyme in which the triphenylmethane derivative can be seen to select for PfdUTPase by way of interactions between the trityl group and the side chains of residues Phe46 and Ile117. Immunofluorescence microscopy studies of parasitized red blood cells reveal that enzyme concentrations are highest during the trophozoite/schizont stages, suggesting that PfdUTPase has a major role in DNA replication. Taken together the data show that PfdUTPase may be considered as an antimalarial drug target. dUTPase as a platform for antimalarial drug design: structural basis for the selectivity of a class of nucleoside inhibitors.,Whittingham JL, Leal I, Nguyen C, Kasinathan G, Bell E, Jones AF, Berry C, Benito A, Turkenburg JP, Dodson EJ, Ruiz Perez LM, Wilkinson AJ, Johansson NG, Brun R, Gilbert IH, Gonzalez Pacanowska D, Wilson KS Structure. 2005 Feb;13(2):329-38. PMID:15698576 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also DUTPase 3D structures

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