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Transmission has been reported in 78 countries, and its control depends on a single drug, praziquantel, which has been used over the past 30\u00a0years. Our work is focused on exploiting target\u2010based drug discovery strategies to develop new therapeutics to treat schistosomiasis. In particular, we are interested in evaluating the enzyme dihydroorotate dehydrogenase (DHODH) as a drug target. DHODH is a flavoenzyme that catalyzes the stereospecific oxidation of (<jats:italic>S<\/jats:italic>)\u2010dihydroorotate (DHO) to orotate during the fourth and only redox step of the <jats:italic>de\u00a0novo<\/jats:italic> pyrimidine nucleotide biosynthetic pathway. Previously, we identified atovaquone, used in the treatment of malaria, and its analogues, as potent and selective inhibitors against <jats:italic>Schistosoma\u00a0mansoni<\/jats:italic> DHODH (<jats:italic>SmDHODH<\/jats:italic>). In the present article, we report the first crystal structure of <jats:italic>SmDHODH<\/jats:italic> in complex with the atovaquone analogue inhibitor 2\u2010((4\u2010fluorophenyl)amino)\u20103\u2010hydroxynaphthalene\u20101,4\u2010dione (QLA). We discuss three major findings: (a) the open conformation of the active site loop and the unveiling of a novel transient druggable pocket for class 2 DHODHs; (b) the presence of a protuberant domain, only present in <jats:italic>Schistosoma<\/jats:italic> spp DHODHs, that was found to control and modulate the dynamics of the inhibitor binding site; (c) a detailed description of an unexpected binding mode for the atovaquone analogue to <jats:italic>Sm<\/jats:italic>DHODH. Our findings contribute to the understanding of the catalytic mechanism performed by class 2 DHODHs and provide the molecular basis for structure\u2010guided design of <jats:italic>Sm<\/jats:italic>DHODH inhibitors.<\/jats:p><\/jats:sec><jats:sec><jats:title>Database<\/jats:title><jats:p>The structural data are available in Protein Data Bank (PDB) database under the accession code number <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/www.rcsb.org\/structure\/6UY4\">6UY4<\/jats:ext-link>.<\/jats:p><\/jats:sec>","DOI":"10.1111\/febs.15367","type":"journal-article","created":{"date-parts":[[2020,5,19]],"date-time":"2020-05-19T22:05:08Z","timestamp":1589925908000},"page":"930-944","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Structural basis for the function and inhibition of dihydroorotate dehydrogenase from <i>Schistosoma\u00a0mansoni<\/i>"],"prefix":"10.1111","volume":"288","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0977-4657","authenticated-orcid":false,"given":"Renan M.","family":"de Mori","sequence":"first","affiliation":[{"name":"Laborat\u00f3rio de Cristalografia de Prote\u00ednas Faculdade de Ci\u00eancias Farmac\u00eauticas de Ribeir\u00e3o Preto Universidade de S\u00e3o Paulo Ribeir\u00e3o Preto Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3172-1156","authenticated-orcid":false,"given":"Mariana A. 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