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.

Structural Basis for Inhibition of ROS-Producing Respiratory Complex I by NADH-OH / Vranas, Marta; Wohlwend, Daniel; Qiu, Danye; Gerhardt, Stefan; Trncik, Christian; Pervaiz, Mehrosh; Ritter, Kevin; Steimle, Stefan; Randazzo, Antonio; Einsle, Oliver; Günther, Stefan; Jessen, Henning J.; Kotlyar, Alexander; Friedrich, Thorsten. - In: ANGEWANDTE CHEMIE. INTERNATIONAL EDITION. - ISSN 1433-7851. - 60:(2021), pp. 27277-27281. [10.1002/anie.202112165]

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

Antonio Randazzo
Membro del Collaboration Group
;
2021

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.
2021
Structural Basis for Inhibition of ROS-Producing Respiratory Complex I by NADH-OH / Vranas, Marta; Wohlwend, Daniel; Qiu, Danye; Gerhardt, Stefan; Trncik, Christian; Pervaiz, Mehrosh; Ritter, Kevin; Steimle, Stefan; Randazzo, Antonio; Einsle, Oliver; Günther, Stefan; Jessen, Henning J.; Kotlyar, Alexander; Friedrich, Thorsten. - In: ANGEWANDTE CHEMIE. INTERNATIONAL EDITION. - ISSN 1433-7851. - 60:(2021), pp. 27277-27281. [10.1002/anie.202112165]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/879901
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