4g6h
Crystal structure of NDH with NADH
Structural highlights
FunctionNDI1_YEAST Catalyzes the oxidation of NADH generated inside the Mitochondrion. Publication Abstract from PubMedThe single-component type-II NADH dehydrogenases (NDH-2s) serve as alternatives to the multisubunit respiratory complex I (type-I NADH dehydrogenase (NDH-1), also called NADH:ubiquinone oxidoreductase; EC 1.6.5.3) in catalysing electron transfer from NADH to ubiquinone in the mitochondrial respiratory chain. The yeast NDH-2 (Ndi1) oxidizes NADH on the matrix side and reduces ubiquinone to maintain mitochondrial NADH/NAD(+) homeostasis. Ndi1 is a potential therapeutic agent for human diseases caused by complex I defects, particularly Parkinson's disease, because its expression restores the mitochondrial activity in animals with complex I deficiency. NDH-2s in pathogenic microorganisms are viable targets for new antibiotics. Here we solve the crystal structures of Ndi1 in its substrate-free, NADH-, ubiquinone- and NADH-ubiquinone-bound states, to help understand the catalytic mechanism of NDH-2s. We find that Ndi1 homodimerization through its carboxy-terminal domain is critical for its catalytic activity and membrane targeting. The structures reveal two ubiquinone-binding sites (UQ(I) and UQ(II)) in Ndi1. NADH and UQ(I) can bind to Ndi1 simultaneously to form a substrate-protein complex. We propose that UQ(I) interacts with FAD to act as an intermediate for electron transfer, and that NADH transfers electrons through this FAD-UQ(I) complex to UQ(II). Together our data reveal the regulatory and catalytic mechanisms of Ndi1 and may facilitate the development or targeting of NDH-2s for potential therapeutic applications. Structural insight into the type-II mitochondrial NADH dehydrogenases.,Feng Y, Li W, Li J, Wang J, Ge J, Xu D, Liu Y, Wu K, Zeng Q, Wu JW, Tian C, Zhou B, Yang M Nature. 2012 Nov 15;491(7424):478-82. doi: 10.1038/nature11541. Epub 2012 Oct 21. PMID:23086143[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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