ArticleProceedings of the National Academy of Sciences of the United States of America2013
Structure of the trypanosome cyanide-insensitive alternative oxidase.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 77 papers.
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Who cites it
77 citing papers in PubMed, 180 citations in OpenAlex.
- Ligand-induced reshaping of the conformational free energy landscape drives dynamic restriction in Trypanosoma brucei alternative oxidase.Journal of computer-aided molecular design · 2026Article
- The diversity of terminal electron acceptors across eukaryotes.Trends in biochemical sciences · 2026Review
- The role of alternative oxidase in the maintenance of cellular redox balance under hypoxia via participation in nitric oxide turnover.Journal of experimental botany · 2025Review
- Uncovering the Unusual Inhibition Mechanism of a Trypanosome Alternative Oxidase Inhibitor Displaying Broad-Spectrum Activity against African Animal Trypanosomes.Journal of medicinal chemistry · 2025Article
- Oversized nanodiscs for combined structural and functional investigation of multicomponent membrane protein systems.Scientific reports · 2025Article
- Review
- Ascofuranone antibiotic is a promising trypanocidal drug for nagana.The Onderstepoort journal of veterinary research · 2024Article
- Genome mining and biosynthetic pathways of marine-derived fungal bioactive natural products.Frontiers in microbiology · 2024Review
- Multifactor transcriptional control of alternative oxidase induction integrates diverse environmental inputs to enable fungal virulence.Nature communications · 2023Article
- The biogenesis and regulation of the plant oxidative phosphorylation system.Plant physiology · 2023Review
- Identification of megacerotonic acid and a quinazoline derivative from Universal Natural Product Database as potential inhibitors ofJournal of biomolecular structure & dynamics · 2023Article
- Identifying antibiotics based on structural differences in the conserved allostery from mitochondrial heme-copper oxidases.Nature communications · 2022Article
- Inhibition of mitosomal alternative oxidase causes lifecycle arrest of early-stage Trachipleistophora hominis meronts during intracellular infection of mammalian cells.PLoS pathogens · 2022Article
- Gallic Acid Alkyl Esters: Trypanocidal and Leishmanicidal Activity, and Target Identification via Modeling Studies.Molecules (Basel, Switzerland) · 2022Article
- Localization and functional characterization of the alternative oxidase in Naegleria.The Journal of eukaryotic microbiology · 2022Article
- Targeting the alternative oxidase (AOX) for human health and food security, a pharmaceutical and agrochemical target or a rescue mechanism?The Biochemical journal · 2022Review
- The identification of alternative oxidase in intermediate host snails of Schistosoma and its potential role in protecting Oncomelania hupensis against niclosamide-induced stress.Parasites & vectors · 2022Article
- Recent Advances in Structural Studies of CytochromeInternational journal of molecular sciences · 2022Review
- Imidazoline- and Benzamidine-Based Trypanosome Alternative Oxidase Inhibitors: Synthesis and Structure-Activity Relationship Studies.ACS medicinal chemistry letters · 2022Article
- Structural and Biophysical Characterization of Purified RecombinantFrontiers in plant science · 2022Article
17 more citing papers are in PubMed but not listed here.
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Authors and funding
18 authors at 6 institutions in 3 countries.
Funding
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.