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Structural insight into the type-II mitochondrialNADH dehydrogenases

The single-component type-IINADHdehydrogenases (NDH-2s) serveas alternatives to the multisubunit respiratory complex I (type-INADH dehydrogenase (NDH-1), also called NADH:ubiquinoneoxidoreductase;EC in catalysing electron transfer fromNADHtoubiquinone in themitochondrial respiratory chain. The yeastNDH-2(Ndi1) oxidizes NADH on the matrix side and reduces ubiquinone tomaintain mitochondrial NADH/NAD1 homeostasis. Ndi1 is a potentialtherapeutic agent for human diseases caused by complex Idefects, particularly Parkinson’s disease, because its expressionrestores the mitochondrial activity in animals with complexI deficiency.NDH-2s in pathogenic microorganisms are viable targets fornew antibiotics. Using MX beamline (BL17U1) at Shanghai Synchrotron Radiation Facility, Maojun Yang group of Tsinghua Universitysolved the crystal structures of Ndi1 in itssubstrate-free, NADH-, ubiquinone- and NADH–ubiquinone-boundstates, to help understand the catalyticmechanism ofNDH-2s. They findthat Ndi1 homodimerization through its carboxy-terminal domain iscritical for its catalytic activity andmembranetargeting. The structuresreveal two ubiquinone-binding sites (UQI and UQII) in Ndi1.NADHand UQI can bind to Ndi1 simultaneously to form a substrate–proteincomplex.They propose that UQI interacts with FAD to act as an intermediatefor electron transfer, and that NADH transfers electronsthrough this FAD–UQI complex to UQII. Together their data revealthe regulatory and catalytic mechanisms of Ndi1 and may facilitatethe development or targeting of NDH-2s for potential therapeuticapplications.


The structure of Ndi1

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