3VVA

Crystal structure of cyanide-insensitive alternative oxidase from Trypanosoma brucei with ascofuranone derivative

Summary for 3VVA

• Entry DOI: 10.2210/pdb3vva/pdb
• Related: 3VV9 3W54
• Descriptor: Alternative oxidase, mitochondrial, FE (III) ION, HYDROXIDE ION, ... (5 entities in total)
• Functional Keywords: helix double, membrane bound diiron protein, oxidase, membrane, oxidoreductase, oxidoreductase-oxidoreductase inhibitor complex, alternative oxidase, oxidoreductase/oxidoreductase inhibitor
• Biological source: Trypanosoma brucei brucei
• Cellular location: Mitochondrion inner membrane; Multi-pass membrane protein (Probable): Q26710
• Total number of polymer chains: 4
• Total formula weight: 152499.35

Authors

Shiba, T.,Kido, Y.,Sakamoto, K.,Inaoka, D.K.,Tsuge, C.,Tatsumi, R.,Balogun, E.O.,Nara, T.,Aoki, T.,Honma, T.,Tanaka, A.,Inoue, M.,Matsuoka, S.,Saimoto, H.,Moore, A.L.,Harada, S.,Kita, K. (deposition date: 2012-07-17, release date: 2013-03-13, Last modification date: 2023-11-08)

Primary citation

Shiba, T.,Kido, Y.,Sakamoto, K.,Inaoka, D.K.,Tsuge, C.,Tatsumi, R.,Takahashi, G.,Balogun, E.O.,Nara, T.,Aoki, T.,Honma, T.,Tanaka, A.,Inoue, M.,Matsuoka, S.,Saimoto, H.,Moore, A.L.,Harada, S.,Kita, K.
Structure of the trypanosome cyanide-insensitive alternative oxidase
Proc.Natl.Acad.Sci.USA, 110:4580-4585, 2013

PubMed Abstract: In addition to haem copper oxidases, all higher plants, some algae, yeasts, molds, metazoans, and pathogenic microorganisms such as Trypanosoma brucei contain an additional terminal oxidase, the cyanide-insensitive alternative oxidase (AOX). AOX is a diiron carboxylate protein that catalyzes the four-electron reduction of dioxygen to water by ubiquinol. In T. brucei, a parasite that causes human African sleeping sickness, AOX plays a critical role in the survival of the parasite in its bloodstream form. Because AOX is absent from mammals, this protein represents a unique and promising therapeutic target. Despite its bioenergetic and medical importance, however, structural features of any AOX are yet to be elucidated. Here we report crystal structures of the trypanosomal alternative oxidase in the absence and presence of ascofuranone derivatives. All structures reveal that the oxidase is a homodimer with the nonhaem diiron carboxylate active site buried within a four-helix bundle. Unusually, the active site is ligated solely by four glutamate residues in its oxidized inhibitor-free state; however, inhibitor binding induces the ligation of a histidine residue. A highly conserved Tyr220 is within 4 Å of the active site and is critical for catalytic activity. All structures also reveal that there are two hydrophobic cavities per monomer. Both inhibitors bind to one cavity within 4 Å and 5 Å of the active site and Tyr220, respectively. A second cavity interacts with the inhibitor-binding cavity at the diiron center. We suggest that both cavities bind ubiquinol and along with Tyr220 are required for the catalytic cycle for O2 reduction.

PubMed: 23487766
DOI: 10.1073/pnas.1218386110

Experimental method

X-RAY DIFFRACTION (2.59 Å)