Structural Basis for Inhibition of ROS‐Producing Respiratory Complex I by NADH‐OH
Marta Vranas, Daniel Wohlwend, Danye Qiu, S. Gerhardt, Christian Trncik, Mehrosh Pervaiz, Kevin Ritter, Stefan Steimle, Antonio Randazzo, Oliver Einsle, Stefan Günther, Henning J. Jessen, Alexander Kotlyar, Thorsten Friedrich
Abstract
NADH:ubiquinone oxidoreductase, respiratory complex I, plays a central role in cellular energy metabolism. As a major source of reactive oxygen species (ROS) it affects ageing and mitochondrial dysfunction. The novel inhibitor NADH-OH 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-ray crystallographic analysis, we report the structure of NADH-OH bound in the active site of a soluble fragment of complex I at 2.0 Å resolution. We have identified key amino acid residues that are specific and essential for binding NADH-OH. Furthermore, the structure sheds light on the specificity of NADH-OH towards the unique Rossmann-fold of complex I and indicates a regulatory role in mitochondrial ROS generation. In addition, NADH-OH acts as a lead-structure for the synthesis of a novel class of ROS suppressors.