Crystal structure of the protein drug urate oxidase-inhibitor complex at 2.05 A resolution.
The gene coding for urate oxidase, an enzyme that catalyzes the oxidation 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 homotetrameric enzyme reveals the existence of a small architectural domain that 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 that now has three members; tetrahydropterin synthase, GTP cyclohydrolase I and urate oxidase. The structure of the active site of urate oxidase around the 8-azaxanthine inhibitor reveals an original mechanism of oxidation that does not require any ions or prosthetic groups.
Colloc'h
N
N
Systèmes Moléculaires et Biologie Structurale, CNRS URA09, Université Paris VI et Paris VII, France.
el Hajji
M
M
Bachet
B
B
L'Hermite
G
G
Schiltz
M
M
Prangé
T
T
Castro
B
B
Mornon
J P
JP
D001231:Aspergillus flavus / Q000201:enzymology; D001665:Binding Sites; D018360:Crystallography, X-Ray; D019281:Dimerization; D004791:Enzyme Inhibitors / Q000737:chemistry; D008958:Models, Molecular; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D014503:Urate Oxidase / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D014970:Xanthines / Q000737:chemistry*
D004791:Enzyme Inhibitors; D014970:Xanthines; C018221:8-azaxanthine; D014503:Urate Oxidase