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The\n                    <jats:italic>Staphylococcus aureus<\/jats:italic>\n                    Stl protein inhibits diverse dUTPases in vitro, but its efficacy in a eukaryotic organism was unknown. We determined the crystal structure of zebrafish dUTPase in complex with the N\u2010terminal Stl fragment to 2.26\u2009\u00c5 resolution, revealing conserved active\u2010site engagement and displacement of the C\u2010terminal arm. Biolayer interferometry confirmed low\u2010nanomolar binding affinity with\n                    <jats:italic>K<\/jats:italic>\n                    <jats:sub>D<\/jats:sub>\n                    \u2009=\u20090.7\u2009nM, and enzyme assays demonstrated ~50% inhibition of zebrafish dUTPase activity at saturating Stl concentrations. These structural and biophysical data establish that Stl forms a tight inhibitory complex with zebrafish dUTPase, prompting us to test whether this interaction can perturb enzyme function in vivo. Microinjection of Stl or its point mutant, retaining dUTPase\u2010inhibitory activity but unable to bind DNA, into fertilized zebrafish oocytes reduces embryo survival to ~60% within 48\u2009h compared to ~90% in controls, demonstrating that lethality depends on dUTPase targeting rather than DNA binding. Accelerated mortality relative to genetic dUTPase knockout indicates that maternally deposited dUTPase supports viability during early cleavage. Stl thus acts as an immediate, proteinaceous dUTPase inhibitor in a living vertebrate, providing a tool to dissect dUTPase function and regulation during embryonic development.\n                  <\/jats:p>","DOI":"10.1002\/pro.70767","type":"journal-article","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T12:21:39Z","timestamp":1789561299000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A bacterial protein inhibitor of\n                    <scp>dUTPase<\/scp>\n                    disrupts zebrafish embryogenesis through a conserved active\u2010site mechanism"],"prefix":"10.1002","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-4501-6663","authenticated-orcid":false,"given":"Vikt\u00f3ria","family":"Perey\u2010Simon","sequence":"first","affiliation":[{"name":"Department of Applied Biotechnology and Food Science, Faculty of Chemical Technology and Biotechnology Budapest University of Technology and Economics  Budapest Hungary"},{"name":"Institute of Molecular Life Sciences HUN\u2010REN Research Centre for Natural Sciences  Budapest Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zo\u00e9 S\u00e1ra","family":"T\u00f3th","sequence":"additional","affiliation":[{"name":"Institute of Molecular Life Sciences HUN\u2010REN Research Centre for Natural Sciences  Budapest Hungary"},{"name":"Doctoral School of Biology, Institute of Biology ELTE E\u00f6tv\u00f6s Lor\u00e1nd University  Budapest Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D\u00e1niel","family":"Dombov\u00e1ri","sequence":"additional","affiliation":[{"name":"Department of Applied Biotechnology and Food Science, Faculty of Chemical Technology and Biotechnology Budapest University of Technology and Economics  Budapest Hungary"},{"name":"Institute of Molecular Life Sciences HUN\u2010REN Research Centre for Natural Sciences  Budapest Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Latifa","family":"Kazzazy","sequence":"additional","affiliation":[{"name":"Doctoral School of Biology, Institute of Biology ELTE E\u00f6tv\u00f6s Lor\u00e1nd University  Budapest Hungary"},{"name":"Department of Genetics ELTE E\u00f6tv\u00f6s Lor\u00e1nd University  Budapest Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4289-1705","authenticated-orcid":false,"given":"M\u00e1t\u00e9","family":"Varga","sequence":"additional","affiliation":[{"name":"Department of Genetics ELTE E\u00f6tv\u00f6s Lor\u00e1nd University  Budapest Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Be\u00e1ta G.","family":"V\u00e9rtessy","sequence":"additional","affiliation":[{"name":"Department of Applied Biotechnology and Food Science, Faculty of Chemical Technology and Biotechnology Budapest University of Technology and Economics  Budapest 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