Structure of the bacterial type II NADH dehydrogenase: a monotopic membrane protein with an essential role in energy generation
Structure of the bacterial type II NADH dehydrogenase: a monotopic membrane protein with an essential role in energy generation
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DOI：
10.1111/mmi.12507
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发表时间：
2014-03-01
影响因子：
3.6
通讯作者：
Cook, Gregory M.
中科院分区：
文献类型：
--
作者：
Heikal, Adam;Nakatani, Yoshio;Cook, Gregory M.
非质子泵送型II型NADH脱氢酶（NDH-2）在细菌的呼吸代谢以及真菌、植物和原生生物的线粒体中起着核心作用。哺乳动物线粒体中缺乏NDH-2及其在重要细菌病原体中的重要性表明，这些酶可能代表了对抗微生物病原体的潜在新药物靶点。在这里，我们报道了热芽孢杆菌在2.5埃分辨率下的细菌NDH-2酶的第一个晶体结构。NDH-2结构揭示了具有独特二聚体界面的同二聚体组织。NDH-2通过两个分离的c端膜锚定区定位到细胞质膜上，这是膜定位和FAD结合所必需的，但不是NDH-2二聚化。比较细菌NDH-2与酵母NADH脱氢酶（Ndi1）的结构，发现细菌酶中醌和NADH的结合位点不重叠。细菌NDH-2结构为基于结构的小分子抑制剂设计建立了框架。
Non-proton pumping type II NADH dehydrogenase (NDH-2) plays a central role in the respiratory metabolism of bacteria, and in the mitochondria of fungi, plants and protists. The lack of NDH-2 in mammalian mitochondria and its essentiality in important bacterial pathogens suggests these enzymes may represent a potential new drug target to combat microbial pathogens. Here, we report the first crystal structure of a bacterial NDH-2 enzyme at 2.5 angstrom resolution from Caldalkalibacillus thermarum. The NDH-2 structure reveals a homodimeric organization that has a unique dimer interface. NDH-2 is localized to the cytoplasmic membrane by two separated C-terminal membrane-anchoring regions that are essential for membrane localization and FAD binding, but not NDH-2 dimerization. Comparison of bacterial NDH-2 with the yeast NADH dehydrogenase (Ndi1) structure revealed non-overlapping binding sites for quinone and NADH in the bacterial enzyme. The bacterial NDH-2 structure establishes a framework for the structure-based design of small-molecule inhibitors.