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As a major source of reactive oxygen species (ROS) it affects ageing and mitochondrial dysfunction. The novel inhibitor NADH\u2010OH specifically blocks NADH oxidation and ROS production by complex I in nanomolar concentrations. Attempts to elucidate its structure by NMR spectroscopy have failed. Here, by using X\u2010ray crystallographic analysis, we report the structure of NADH\u2010OH bound in the active site of a soluble fragment of complex I at 2.0\u2005\u00c5 resolution. We have identified key amino acid residues that are specific and essential for binding NADH\u2010OH. Furthermore, the structure sheds light on the specificity of NADH\u2010OH towards the unique Rossmann\u2010fold of complex I and indicates a regulatory role in mitochondrial ROS generation. In addition, NADH\u2010OH acts as a lead\u2010structure for the synthesis of a novel class of ROS suppressors.<\/jats:p>","DOI":"10.1002\/anie.202112165","type":"journal-article","created":{"date-parts":[[2021,10,8]],"date-time":"2021-10-08T03:53:29Z","timestamp":1633665209000},"page":"27277-27281","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Structural Basis for Inhibition of ROS\u2010Producing Respiratory Complex I by NADH\u2010OH"],"prefix":"10.1002","volume":"60","author":[{"given":"Marta","family":"Vranas","sequence":"first","affiliation":[{"name":"Institute of Biochemistry University of Freiburg  79104 Freiburg Germany"},{"name":"Magellan Biologics &amp; Consulting  4200-135 Porto Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6782-5822","authenticated-orcid":false,"given":"Daniel","family":"Wohlwend","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry University of Freiburg  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