The crystal structure of Trypanosoma cruzi dUTPase reveals a novel dUTP/dUDP binding fold.
dUTPase is an essential enzyme involved with nucleotide metabolism and replication. We report here the X-ray structure of Trypanosoma cruzi dUTPase in its native conformation and as a complex with dUDP. These reveal a novel protein fold that displays no structural similarities to previously described dUTPases. The molecular unit is a dimer with two active sites. Nucleotide binding promotes extensive structural rearrangements, secondary structure remodeling, and rigid body displacements of 20 A or more, which effectively bury the substrate within the enzyme core for the purpose of hydrolysis. The molecular complex is a trapped enzyme-substrate arrangement which clearly demonstrates structure-induced specificity and catalytic potential. This enzyme is a novel dUTPase and therefore a potential drug target in the treatment of Chagas' disease.
Harkiolaki
Maria
M
Structural Biology Laboratory, Department of Chemistry, University of York, Heslington, York YO10 5YW, UK.
Dodson
Eleanor J
EJ
Bernier-Villamor
Victor
V
Turkenburg
Johan P
JP
González-Pacanowska
Dolores
D
Wilson
Keith S
KS
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D003856:Deoxyuracil Nucleotides / Q000737:chemistry*; D019281:Dimerization; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008274:Magnesium / Q000737:chemistry*; D008969:Molecular Sequence Data; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D011755:Pyrophosphatases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D014349:Trypanosoma cruzi / Q000201:enzymology*
D003856:Deoxyuracil Nucleotides; D004791:Enzyme Inhibitors; D011755:Pyrophosphatases; C020020:dUTP pyrophosphatase; D008274:Magnesium