CRYSTAL-STRUCTURE OF THE PROTEIN DRUG URATE OXIDASE-INHIBITOR COMPLEXAT 2.05 ANGSTROM RESOLUTION

The gene coding for urate oxidase, an enzyme that catalyzes the oxidat ion of uric acid to allantoin, is inactivated in humans. Consequently, urate oxidase is used as a protein drug to overcome severe disorders induced by uric acid accumulation. The structure of the active homotet rameric enzyme reveals the existence of a small architectural domain t hat we call T-fold (for tunnelling-fold) domain. It assembles to form a perfect unusual dimeric alpha 8 beta 16 barrel. Urate oxidase may be the archetype of an expanding new family of tunnel-shaped proteins th at now has three members; tetrahydropterin synthase, CTP cyclohydrolas e I and urate oxidase. The structure of the active site of urate oxida se around the 8-azaxanthine inhibitor reveals an original mechanism of oxidation that does not require any ions or prosthetic groups.