Structural Basis for Inhibition of ROS-Producing Respiratory Complex I by NADH-OH.
Angew Chem Int Ed Engl
; 60(52): 27277-27281, 2021 12 20.
Article
en En
| MEDLINE
| ID: mdl-34612584
ABSTRACT
NADHubiquinone 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 2.0â
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Complejo I de Transporte de Electrón
/
Inhibidores Enzimáticos
/
NAD
Límite:
Humans
Idioma:
En
Revista:
Angew Chem Int Ed Engl
Año:
2021
Tipo del documento:
Article
País de afiliación:
Alemania