来自清华大学生命科学学院、中科院植物研究所的研究人员首次报道了II型NADH-泛醌氧化还原酶Ndi1的晶体结构,并对其生理功能和工作机制进行了详细的研究。

-2012年11月15日《自然》

中文翻译


【题目】II型线粒体NADH脱氢酶的结构

【译文】单组份II型NADH脱氢酶(NDH-2s)是多亚基呼吸链复合物 I (I型NADH脱氢酶(NDH-1),也称为NADH:辅酶Q氧化还原酶; EC1.6.5.3)的替代,多亚基呼吸链复合物 I是催化电子从NADH转移至线粒体呼吸链中辅酶Q的组分。酵母NDH-2 (Ndi1)氧化NADH并减少辅酶Q并维持线粒体NADH/NAD+稳态。Ndi1是复合物I缺陷引起的人类疾病的潜在治疗药物,尤其是帕金森病,因为它的表达可以恢复复合物I缺陷动物的线粒体活性。病原微生物中NDH-2s是新抗生素的靶点。本研究解析了Ndi1无底物、NADH-、辅酶Q和NADH-辅酶Q结合状态,以辅助理解NDH-2s的催化机制。我们发现Ndi1羧基端结构域Ndi1同源二聚物通过其羧基端结构域对于其催化活性和膜靶向至关重要。该结构揭示了Ndi1中两种辅酶Q结合位点(UQI和UQII)。NADH和UQI可以同时与Ndi1结合,形成一种底物-蛋白复合物。我们认为,UQI与FAD相互作用充当电子转移中间体的作用,而且NADH是通过这种FAD–UQI复合物向UQII转移电子。综合这些数据揭示Ndi1的调控和催化机制,可能有助于NDH-2s潜在治疗应用的靶向或发展。

英文原稿


[Title]: Structural insight into the type-II mitochondrial NADH dehydrogenases

[Authors]:Yue Feng,1, 5 Wenfei Li,1, 5 Jian Li,1, 5 Jiawei Wang,1 Jingpeng Ge,1 Duo Xu,1 Yanjing Liu,2 Kaiqi Wu,3 Qingyin Zeng,2 Jia-Wei Wu,1 Changlin Tian,3, 4 Bing Zhou1 & Maojun Yang1

[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; EC1.6.5.3) 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 (UQI and UQII) in Ndi1. NADH and UQI can bind to Ndi1 simultaneously to form a substrate–protein complex. We propose that UQI interacts with FAD to act as an intermediate for electron transfer, and that NADH transfers electrons through this FAD–UQI complex to UQII. 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.

原文地址

http://www.nature.com/nature/journal/v491/n7424/full/nature11541.html

 

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