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

Angew Chem Int Ed Engl. 2021 Dec 20;60(52):27277-27281. doi: 10.1002/anie.202112165. Epub 2021 Nov 15.


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.

Keywords: NADH:ubiquinone oxidoreductase; electron transport; inhibitors; reactive oxygen species; structural biology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aquifex / enzymology
  • Bacterial Proteins / antagonists & inhibitors
  • Bacterial Proteins / chemistry
  • Bacterial Proteins / metabolism
  • Electron Transport Complex I / antagonists & inhibitors*
  • Electron Transport Complex I / chemistry
  • Electron Transport Complex I / metabolism
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Hydrogen Bonding
  • Models, Molecular
  • NAD / analogs & derivatives*
  • NAD / chemistry
  • NAD / metabolism
  • NAD / pharmacology
  • Protein Binding


  • Bacterial Proteins
  • Enzyme Inhibitors
  • NAD
  • Electron Transport Complex I

Supplementary concepts

  • Aquifex aeolicus