title: The crystal structure of Trypanosoma cruzi dUTPase reveals a novel dUTP/dUDP binding fold.
abstract: 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.
authors.affiliation: Structural Biology Laboratory, Department of Chemistry, University of York, Heslington, York YO10 5YW, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Harkiolaki
authors.forename: Eleanor J
authors.initials: EJ
authors.lastname: Dodson
authors.forename: Victor
authors.initials: V
authors.lastname: Bernier-Villamor
authors.forename: Johan P
authors.initials: JP
authors.lastname: Turkenburg
authors.forename: Dolores
authors.initials: D
authors.lastname: González-Pacanowska
authors.forename: Keith S
authors.initials: KS
authors.lastname: Wilson
mesh_terms: 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*
chemical_list: D003856:Deoxyuracil Nucleotides; D004791:Enzyme Inhibitors; D011755:Pyrophosphatases; C020020:dUTP pyrophosphatase; D008274:Magnesium