4G74: Crystal Structure of NDH With Quinone

Citation:
Abstract
The 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.
PDB ID: 4G74Download
MMDB ID: 104265
PDB Deposition Date: 2012/7/19
Updated in MMDB: 2012/12 
Experimental Method:
x-ray diffraction
Resolution: 2.48  Å
Source Organism:
Similar Structures:
Biological Unit for 4G74: dimeric; determined by author and by software (PISA)
Molecular Components in 4G74
Label Count Molecule
Proteins (2 molecules)
2
Rotenone-insensitive Nadh-ubiquinone Oxidoreductase, Mitochondrial(Gene symbol: NDI1)
Molecule annotation
Chemicals (21 molecules)
1
4
2
4
3
11
4
2
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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