{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T17:41:36Z","timestamp":1791394896538,"version":"4.3.3"},"reference-count":47,"publisher":"National Academy of Sciences","issue":"12","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2013,3,19]]},"abstract":"<jats:p>\n                    In addition to haem copper oxidases, all higher plants, some algae, yeasts, molds, metazoans, and pathogenic microorganisms such as\n                    <jats:italic>Trypanosoma brucei<\/jats:italic>\n                    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\n                    <jats:italic>T. brucei,<\/jats:italic>\n                    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 \u00c5 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 \u00c5 and 5 \u00c5 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 O\n                    <jats:sub>2<\/jats:sub>\n                    reduction.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1218386110","type":"journal-article","created":{"date-parts":[[2013,3,5]],"date-time":"2013-03-05T06:32:33Z","timestamp":1362465153000},"page":"4580-4585","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":175,"title":["Structure of the trypanosome cyanide-insensitive alternative oxidase"],"prefix":"10.1073","volume":"110","author":[{"given":"Tomoo","family":"Shiba","sequence":"first","affiliation":[{"name":"Department of Biomedical Chemistry, Graduate School of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasutoshi","family":"Kido","sequence":"additional","affiliation":[{"name":"Department of Biomedical Chemistry, Graduate School of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimitoshi","family":"Sakamoto","sequence":"additional","affiliation":[{"name":"Department of Biomedical Chemistry, Graduate School of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel Ken","family":"Inaoka","sequence":"additional","affiliation":[{"name":"Department of Biomedical Chemistry, Graduate School of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiaki","family":"Tsuge","sequence":"additional","affiliation":[{"name":"Department of Biomedical Chemistry, Graduate School of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryoko","family":"Tatsumi","sequence":"additional","affiliation":[{"name":"Department of Biomedical Chemistry, Graduate School of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gen","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Department of Applied Biology, Graduate School of Science and Technology, Kyoto Institute of Technology, Kyoto 606-8585, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuel Oluwadare","family":"Balogun","sequence":"additional","affiliation":[{"name":"Department of Biomedical Chemistry, Graduate School of Medicine, and"},{"name":"Department of Applied Biology, Graduate School of Science and Technology, Kyoto Institute of Technology, Kyoto 606-8585, Japan;"},{"name":"Department of Biochemistry, Ahmadu Bello University, Zaria 2222, Nigeria;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Nara","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Parasitology, Juntendo University School of Medicine, Tokyo 113-8421, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Aoki","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Parasitology, Juntendo University School of Medicine, Tokyo 113-8421, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teruki","family":"Honma","sequence":"additional","affiliation":[{"name":"Systems and Structural Biology Center, RIKEN, Tsurumi, Yokohama 230-0045, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akiko","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Systems and Structural Biology Center, RIKEN, Tsurumi, Yokohama 230-0045, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masayuki","family":"Inoue","sequence":"additional","affiliation":[{"name":"Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shigeru","family":"Matsuoka","sequence":"additional","affiliation":[{"name":"Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Saimoto","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University, Tottori 680-8552, Japan; 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