title: Crystal structures of T. vivax nucleoside hydrolase in complex with new potent and specific inhibitors.
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.
authors.affiliation: Structural Biology Brussels, Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, Belgium. wversees@vub.ac.be
authors.forename: Wim
authors.initials: W
authors.lastname: Versées
authors.forename: Annelies
authors.initials: A
authors.lastname: Goeminne
authors.forename: Maya
authors.initials: M
authors.lastname: Berg
authors.forename: An
authors.initials: A
authors.lastname: Vandemeulebroucke
authors.forename: Achiel
authors.initials: A
authors.lastname: Haemers
authors.forename: Koen
authors.initials: K
authors.lastname: Augustyns
authors.forename: Jan
authors.initials: J
authors.lastname: Steyaert
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D009699:N-Glycosyl Hydrolases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D011487:Protein Conformation; D016689:Trypanosoma vivax / Q000201:enzymology*
chemical_list: D004791:Enzyme Inhibitors; D009699:N-Glycosyl Hydrolases