The studies of reaction mechanism of cyanide-insensitive alternative oxidase from Trypanosoma brucei (TAO), a promising drug target

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Trypanosoma brucei is the causative agent of human African sleeping sickness (trypanosomiasis). The cyanide-insensitive alternative oxidase from T. brucei (TAO) is a membrane-bound diiron carboxylate protein which is located on the inner surface of the inner mitochondrial membrane Since TAO is absent from the mammalian host it is a promising target for the development of anti-trypanosomal drugs.I have reported on the first crystal structure of TAO in the presence and absence of an ascofuranone (AF)-derivative at 2.6 and 2.85 angstrom resolution, respectively (Shiba T et al. Proc. Natl. Acad. Sci. USA, 2013). The structures reveal a membrane binding region and an active-site containing 4 glutamate and 2 histidine residues which are buried in a 4-helix bundle. The binding of the AF-inhibitor results in major conformational changes at the active site.