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Here we report cryo-electron microscopy structures of an apicomplexan III\n                    <jats:sub>2<\/jats:sub>\n                    \u2013IV supercomplex and of the drug target complex III\n                    <jats:sub>2<\/jats:sub>\n                    . The supercomplex structure reveals how clade-specific subunits form an apicomplexan-conserved III\n                    <jats:sub>2<\/jats:sub>\n                    \u2013IV interface with a unique, kinked architecture, suggesting that supercomplexes evolved independently in different eukaryotic lineages. A knockout resulting in supercomplex disassembly challenges the proposed role of III\n                    <jats:sub>2<\/jats:sub>\n                    \u2013IV in electron transfer efficiency as suggested for mammals. Nevertheless, knockout analysis indicates that III\n                    <jats:sub>2<\/jats:sub>\n                    \u2013IV is critical for parasite fitness. The complexes from the model parasite\n                    <jats:italic>Toxoplasma gondii<\/jats:italic>\n                    were inhibited with the antimalarial atovaquone, revealing interactions underpinning species specificity. They were also inhibited with endochin-like quinolone (ELQ)-300, an inhibitor in late-stage preclinical development. Notably, in the apicomplexan binding site, ELQ-300 is flipped compared with related compounds in the mammalian enzyme. On the basis of the binding modes and parasite-specific interactions discovered, we designed more potent ELQs with subnanomolar activity against\n                    <jats:italic>T.<\/jats:italic>\n                    \u2009\n                    <jats:italic>gondii<\/jats:italic>\n                    . Our findings reveal critical evolutionary differences in the role of supercomplexes in mitochondrial biology and provide insight into cytochrome\n                    <jats:italic>b<\/jats:italic>\n                    inhibition, informing future drug discovery.\n                  <\/jats:p>","DOI":"10.1038\/s41594-025-01531-7","type":"journal-article","created":{"date-parts":[[2025,5,19]],"date-time":"2025-05-19T05:02:27Z","timestamp":1747630947000},"page":"1424-1433","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Structure, assembly and inhibition of the Toxoplasma gondii respiratory chain supercomplex"],"prefix":"10.1038","volume":"32","author":[{"given":"Andrew E.","family":"MacLean","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7878-1463","authenticated-orcid":false,"given":"Shikha","family":"Shikha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariana","family":"Ferreira Silva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3090-9314","authenticated-orcid":false,"given":"Max J.","family":"Gramelspacher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron","family":"Nilsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine M.","family":"Liebman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sovitj","family":"Pou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rolf W.","family":"Winter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9635-1021","authenticated-orcid":false,"given":"Amit","family":"Meir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1343-5279","authenticated-orcid":false,"given":"Michael K.","family":"Riscoe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6098-1520","authenticated-orcid":false,"given":"J. 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