The Crystal Structure of Trypanosoma cruzi dUTPase Reveals a Novel dUTP/dUDP Binding Fold

• Published in: Structure (London) 2004-01, Vol.12 (1), p.41-53
• Main Authors: Harkiolaki, Maria, Dodson, Eleanor J, Bernier-Villamor, Victor, Turkenburg, Johan P, González-Pacanowska, Dolores, Wilson, Keith S
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Binding Sites; Crystallography, X-Ray; Deoxyuracil Nucleotides - chemistry; Dimerization; Enzyme Inhibitors - pharmacology; Humans; Magnesium - chemistry; Molecular Sequence Data; Protein Binding; Protein Structure, Quaternary; Pyrophosphatases - antagonists & inhibitors; Pyrophosphatases - chemistry; Trypanosoma cruzi; Trypanosoma cruzi - enzymology
• ISSN: 0969-2126; 1878-4186
• DOI: 10.1016/j.str.2003.11.016

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 Å 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.