1VYQ

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

Summary for 1VYQ

• Entry DOI: 10.2210/pdb1vyq/pdb
• Descriptor: DEOXYURIDINE 5'-TRIPHOSPHATE NUCLEOTIDOHYDROLASE, 2,3-DEOXY-3-FLUORO-5-O-TRITYLURIDINE (3 entities in total)
• Functional Keywords: drug design, plasmodium falciparum, dutpase, deoxyuridine nucleotidohydrolase, malaria, hydrolase
• Biological source: PLASMODIUM FALCIPARUM
• Total number of polymer chains: 3
• Total formula weight: 60227.05

Authors

Whittingham, J.L.,Leal, I.,Kasinathan, G.,Nguyen, C.,Bell, E.,Jones, A.F.,Berry, C.,Benito, A.,Turkenburg, J.P.,Dodson, E.J.,Ruiz Perez, L.M.,Wilkinson, A.J.,Johansson, N.G.,Brun, R.,Gilbert, I.H.,Gonzalez Pacanowska, D.,Wilson, K.S. (deposition date: 2004-05-05, release date: 2005-05-26, Last modification date: 2023-12-13)

Primary citation

Whittingham, J.L.,Leal, I.,Nguyen, C.,Kasinathan, G.,Bell, E.,Jones, A.F.,Berry, C.,Benito, A.,Turkenburg, J.P.,Dodson, E.J.,Ruiz Perez, L.M.,Wilkinson, A.J.,Johansson, N.G.,Brun, R.,Gilbert, I.H.,Gonzalez Pacanowska, D.,Wilson, K.S.
Dutpase as a Platform for Antimalarial Drug Design: Structural Basis for the Selectivity of a Class of Nucleoside Inhibitors.
Structure, 13:329-, 2005

PubMed 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.

PubMed: 15698576
DOI: 10.1016/J.STR.2004.11.015

Experimental method

X-RAY DIFFRACTION (2.4 Å)