Crystal Structure of the Trypanosomal Cyanide-Insensitive Alternative Oxidase in Complex with Drug Candidates for African Trypanosomiasis

Abstract

The cyanide-insensitive alternative oxidase （AOX） is a diiron carboxylate protein that catalyzes the four-electron reduction of dioxygen to water by ubiquinol. In Trypanosoma brucei, a parasite that causes human African sleeping sickness, AOX plays a critical role in the survival of the parasite in its bloodstream form. Since AOX is absent from mammals, this protein represents a novel and promising therapeutic target. We determined the first crystal structures of the trypanosomal alternative oxidase in the absence and presence of ascofuranone and its derivatives, which are drug candidates for African trypanosomiasis. All structures reveal that AOX is a homodimer with a non-haem diiron carboxylate active-site buried within a four-helix bundle.