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Structural and mechanistic insights into Streptococcus pneumoniae NADPH oxidase

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Dubach,  Victor R. A.       
Redox and Metalloprotein Research Group, Max Planck Institute of Biophysics, Max Planck Society;
IMPRS-CBP, Max Planck Institute of Biophysics, Max Planck Society;

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San Segundo-Acosta,  Pablo
Redox and Metalloprotein Research Group, Max Planck Institute of Biophysics, Max Planck Society;

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Murphy,  Bonnie J.       
Redox and Metalloprotein Research Group, Max Planck Institute of Biophysics, Max Planck Society;

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Citation

Dubach, V. R. A., San Segundo-Acosta, P., & Murphy, B. J. (2024). Structural and mechanistic insights into Streptococcus pneumoniae NADPH oxidase. Nature Structural & Molecular Biology, 31(11), 1769-1777. doi:10.1038/s41594-024-01348-w.


Cite as: https://hdl.handle.net/21.11116/0000-000F-9930-E
Abstract
Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs) have a major role in the physiology of eukaryotic cells by mediating reactive oxygen species production. Evolutionarily distant proteins with the NOX catalytic core have been found in bacteria, including Streptococcus pneumoniae NOX (SpNOX), which is proposed as a model for studying NOXs because of its high activity and stability in detergent micelles. We present here cryo-electron microscopy structures of substrate-free and nicotinamide adenine dinucleotide (NADH)-bound SpNOX and of NADPH-bound wild-type and F397A SpNOX under turnover conditions. These high-resolution structures provide insights into the electron-transfer pathway and reveal a hydride-transfer mechanism regulated by the displacement of F397. We conducted structure-guided mutagenesis and biochemical analyses that explain the absence of substrate specificity toward NADPH and suggest the mechanism behind constitutive activity. Our study presents the structural basis underlying SpNOX enzymatic activity and sheds light on its potential in vivo function.