Structural Basis for Inhibition of ROS‐Producing Respiratory Complex I by NADH‐OH

NADH:ubiquinone oxidoreductase, respiratory complex I, plays a central role in cellular energy metabolism. As major source of reactive oxygen species (ROS) it affects ageing and mitochondrial dysfunction. The novel inhibitor NADH-OH specifically blocks NADH oxidation ROS production by I nanomolar concentrations. Attempts to elucidate its structure NMR spectroscopy have failed. Here, using X-ray crystallographic analysis, we report the bound active site soluble fragment at 2.0 Å resolution. We identified key amino acid residues that are specific essential for binding NADH-OH. Furthermore, sheds light on specificity towards unique Rossmann-fold indicates regulatory generation. In addition, acts as lead-structure synthesis class suppressors.