Crystal structures of T. vivax nucleoside hydrolase in complex with new potent and specific inhibitors.

TitleCrystal structures of T. vivax nucleoside hydrolase in complex with new potent and specific inhibitors.
Publication TypeJournal Article
Year of Publication2009
AuthorsVersées, W., A. Goeminne, M. Berg, A. Vandemeulebroucke, A. Haemers, K. Augustyns, and J. Steyaert
JournalBiochim Biophys Acta
Volume1794
Issue6
Pagination953-60
Date Published2009 Jun
ISSN0006-3002
KeywordsAnimals, Crystallography, X-Ray, Enzyme Inhibitors, Models, Molecular, N-Glycosyl Hydrolases, Protein Conformation, Trypanosoma vivax
Abstract

Diseases caused by parasitic protozoa remain a major health problem, mainly due to old toxic drugs and rising drug resistance. Nucleoside hydrolases are key enzymes of the purine salvage pathway of parasites from the Trypanosomatidae family and are considered as possible drug targets. N-Arylmethyl substituted iminoribitols have been developed as selective nanomolar affinity inhibitors against the purine-specific nucleoside hydrolase of Trypanosoma vivax. The current paper describes the crystal structures of the T. vivax nucleoside hydrolase in complex with two of these inhibitors, to 1.3 and 1.85 A resolution. These high resolution structures provide an accurate picture of the mode of binding of these inhibitors and their mechanism of transition-state mimicry, and are valuable tools to guide further inhibitor design. Comparison of the current structures with previously solved structures of the enzyme in complex with ground-state and transition-state-analogue inhibitors also allows for the elucidation of a detailed molecular mechanism of active-site loop opening/closing. These loop movements can be coupled to the complex kinetic mechanism of the T. vivax nucleoside hydrolase.

DOI10.1016/j.bbapap.2009.02.011
Alternate JournalBiochim. Biophys. Acta
PubMed ID19281874
Research group: