The Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Keith Peters Building, Cambridge Biomedical Campus, Cambridge, UK.
Structura Biotechnology Inc., Toronto, Canada.
Nat Commun. 2024 Oct 29;15(1):9340. doi: 10.1038/s41467-024-53679-3.
Respiratory complex I is pivotal for cellular energy conversion, harnessing energy from NADH:ubiquinone oxidoreduction to drive protons across energy-transducing membranes for ATP synthesis. Despite detailed structural information on complex I, its mechanism of catalysis remains elusive due to lack of accompanying functional data for comprehensive structure-function analyses. Here, we present the 2.3-Å resolution structure of complex I from the α-proteobacterium Paracoccus denitrificans, a close relative of the mitochondrial progenitor, in phospholipid-bilayer nanodiscs. Three eukaryotic-type supernumerary subunits (NDUFS4, NDUFS6 and NDUFA12) plus a novel L-isoaspartyl-O-methyltransferase are bound to the core complex. Importantly, the enzyme is in a single, homogeneous resting state that matches the closed, turnover-ready (active) state of mammalian complex I. Our structure reveals the elements that stabilise the closed state and completes P. denitrificans complex I as a unified platform for combining structure, function and genetics in mechanistic studies.
呼吸复合物 I 是细胞能量转换的关键，它利用 NADH：泛醌氧化还原产生的能量，将质子跨能量传递膜推动，以合成 ATP。尽管对复合物 I 的结构有详细的了解，但由于缺乏伴随的功能数据，其催化机制仍然难以捉摸，无法进行全面的结构-功能分析。在这里，我们在磷脂双层纳米盘中展示了来自α变形菌脱氮副球菌的复合物 I 的 2.3 Å 分辨率结构，该菌是线粒体前体的近亲。三个真核型多余亚基（NDUFS4、NDUFS6 和 NDUFA12）加上一种新型 L-异天冬氨酰-O-甲基转移酶与核心复合物结合。重要的是，该酶处于单一的、同质的静止状态，与哺乳动物复合物 I 的封闭、周转准备（活性）状态相匹配。我们的结构揭示了稳定封闭状态的要素，并完成了脱氮副球菌复合物 I 的结构，为在机制研究中结合结构、功能和遗传学提供了一个统一的平台。
