Structure of inhibitor-bound mammalian complex I.
Structure of inhibitor-bound mammalian complex I.
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DOI：
10.1038/s41467-020-18950-3
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发表时间：
2020-10-16
影响因子：
16.6
通讯作者：
Hirst J
中科院分区：
文献类型：
--
作者：
Bridges HR;Fedor JG;Blaza JN;Di Luca A;Jussupow A;Jarman OD;Wright JJ;Agip AA;Gamiz-Hernandez AP;Roessler MM;Kaila VRI;Hirst J
呼吸复合体I （NADH：泛醌氧化还原酶）从氧化NADH和还原泛醌中捕获自由能，驱动质子穿过线粒体内膜，并为氧化磷酸化提供动力。最近的冷冻电镜分析已经产生了哺乳动物复合体的近乎完整的模型，但其远程能量耦合机制的分子原理仍有争议。在这里，我们描述了3.0-Å分辨率低温电镜结构的复合物I从小鼠心脏线粒体与底物样抑制剂，piericidin a，结合在泛素结合活性位点。我们将结构分析与功能和计算研究相结合，以证明竞争性抑制剂结合姿势，并提供证据表明两个抑制剂分子在长底物结合通道中端到端结合。我们的研究结果揭示了抑制和底物还原机制的信息，这些信息对于理解哺乳动物复合体I的能量转导原理至关重要。呼吸复合体I （NADH：泛醌氧化还原酶）是一个大的氧化还原驱动的质子泵，在线粒体中启动呼吸。在这里，作者展示了来自小鼠心脏线粒体的复合物I的3.0 Å低温电镜结构，泛素类似物抑制剂piericidin A结合在活性位点，通过动力学测量和MD模拟，他们进一步表明这种抑制剂对天然泛素-10底物具有竞争性。
Respiratory complex I (NADH:ubiquinone oxidoreductase) captures the free energy from oxidising NADH and reducing ubiquinone to drive protons across the mitochondrial inner membrane and power oxidative phosphorylation. Recent cryo-EM analyses have produced near-complete models of the mammalian complex, but leave the molecular principles of its long-range energy coupling mechanism open to debate. Here, we describe the 3.0-Å resolution cryo-EM structure of complex I from mouse heart mitochondria with a substrate-like inhibitor, piericidin A, bound in the ubiquinone-binding active site. We combine our structural analyses with both functional and computational studies to demonstrate competitive inhibitor binding poses and provide evidence that two inhibitor molecules bind end-to-end in the long substrate binding channel. Our findings reveal information about the mechanisms of inhibition and substrate reduction that are central for understanding the principles of energy transduction in mammalian complex I. The respiratory complex I (NADH:ubiquinone oxidoreductase) is a large redox-driven proton pump that initiates respiration in mitochondria. Here, the authors present the 3.0 Å cryo-EM structure of complex I from mouse heart mitochondria with the ubiquinone-analogue inhibitor piericidin A bound in the active site and with kinetic measurements and MD simulations they further show that this inhibitor acts competitively against the native ubiquinone-10 substrate.
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影响因子：
48
作者：
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作者：
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