1VYQ: Novel Inhibitors Of Plasmodium Falciparum Dutpase Provide A Platform For Anti-Malarial Drug Design

Citation:
Abstract
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.
PDB ID: 1VYQDownload
MMDB ID: 33197
PDB Deposition Date: 2004/5/5
Updated in MMDB: 2012/10
Experimental Method:
x-ray diffraction
Resolution: 2.4  Å
Source Organism:
Similar Structures:
Biological Unit for 1VYQ: trimeric; determined by author and by software (PQS)
Molecular Components in 1VYQ
Label Count Molecule
Proteins (3 molecules)
3
Deoxyuridine 5'-triphosphate Nucleotidohydrolase
Molecule annotation
Chemicals (3 molecules)
1
3
* Click molecule labels to explore molecular sequence information.

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