2018
DOI: 10.1038/s41598-018-20775-6
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Ubiquinone binding site of yeast NADH dehydrogenase revealed by structures binding novel competitive- and mixed-type inhibitors

Abstract: Yeast Ndi1 is a monotopic alternative NADH dehydrogenase. Its crystal structure in complex with the electron acceptor, ubiquinone, has been determined. However, there has been controversy regarding the ubiquinone binding site. To address these points, we identified the first competitive inhibitor of Ndi1, stigmatellin, along with new mixed-type inhibitors, AC0-12 and myxothiazol, and thereby determined the crystal structures of Ndi1 in complexes with the inhibitors. Two separate binding sites of stigmatellin, … Show more

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Cited by 19 publications
(12 citation statements)
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“…Five ETC dehydrogenases are conserved in the genome of E. tenella , which are the NDH-2, Complex II, MQO, G3PDH, and DHODH (Figures S1–S5). NDH-2 (Figure S1) is an enzyme with activity equivalent to respiratory complex I, but devoid of proton-pump activity and is required to re-oxidize NADH generated by mitochondrial pathways, such as the tricarboxylic acid (TCA) cycle [29]. Complex II is the only membrane bound enzyme from the TCA cycle in mammals and catalyzes the electron transfer from succinate to quinone (SQR) or from reduced quinol to fumarate (QFR) [7,24,26,30].…”
Section: Resultsmentioning
confidence: 99%
See 1 more Smart Citation
“…Five ETC dehydrogenases are conserved in the genome of E. tenella , which are the NDH-2, Complex II, MQO, G3PDH, and DHODH (Figures S1–S5). NDH-2 (Figure S1) is an enzyme with activity equivalent to respiratory complex I, but devoid of proton-pump activity and is required to re-oxidize NADH generated by mitochondrial pathways, such as the tricarboxylic acid (TCA) cycle [29]. Complex II is the only membrane bound enzyme from the TCA cycle in mammals and catalyzes the electron transfer from succinate to quinone (SQR) or from reduced quinol to fumarate (QFR) [7,24,26,30].…”
Section: Resultsmentioning
confidence: 99%
“…DHODH is the rate-limiting step in the pyrimidine de novo biosynthesis pathway and is required to generate UMP, the building block of DNA and RNA necessary to sustain life [35,36]. NDH-2 and MQO are not conserved in the animal kingdom and are considered as potential drug targets for the development of new antibiotics, and antifungal and antiparasitic agents [13,14,29].…”
Section: Resultsmentioning
confidence: 99%
“…the hydrophobic cavity extending away from the quinone-binding tunnel) for the rational design of new NDH-2 inhibitors. Note that during the peer-review process of this article, another group reported crystal structures of Ndi1 with three Q-site inhibitors (5YJW, 5YJX, and 5YJY) [ 46 ].…”
Section: Discussionmentioning
confidence: 99%
“…From their superimposition, a common cavity hosting an FAD molecule and a NADH molecule is observed. 4g73.pdb hosts a quinone derivative, whereas 5yjw.pdb [46] hosts a stigmatellin bound at the same level of the quinone-binding region. Notably, stigmatellin is known as a competitive NADH-dehydrogenase inhibitor [47] (Figure 4).…”
Section: Sampling Of Homologous-crystallized Structures By Folding Rementioning
confidence: 99%