Redox-induced activation of the proton pump in the respiratory complex I
Redox-induced activation of the proton pump in the respiratory complex I
复制标题
氧化还原诱导的呼吸复合物 I 中质子泵的激活
DOI：
10.1073/pnas.1503761112
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Kaila VRI
中科院分区：
文献类型：
--
作者：
Sharma V;Belevich G;Gamiz-Hernandez AP;Vattulainen I;Wikström M;Hummer G;Kaila VRI
复合物I在线粒体和细菌的呼吸链中作为氧化还原连接的质子泵，由NADH还原醌（Q）驱动。值得注意的是，Q还原位点和最远的质子通道之间的距离延伸了近200 μ m。为了阐明这种远程耦合的分子起源，我们应用大规模分子模拟和一个关键残基的定点突变实验相结合。在混合量子力学/分子力学模拟中，我们观察到，减少Q耦合到其本地质子化的His-38/Asp-139离子对和Tyr-87的亚基Nqo 4。原子经典分子动力学模拟进一步表明，形成的醌醇（QH 2）触发快速解离的阴离子天冬氨酸-139对膜结构域的夫妇在网络中的保守带电残基的构象变化。定点诱变数据证实了Asp-139的重要性;突变为天冬酰胺后，Q还原酶活性被抑制75%。目前的结果，再加上早期的生物化学数据，表明在复杂的I的质子泵被激活的静电和构象转变的独特组合。
Complex I functions as a redox-linked proton pump in the respiratory chains of mitochondria and bacteria, driven by the reduction of quinone (Q) by NADH. Remarkably, the distance between the Q reduction site and the most distant proton channels extends nearly 200 Å. To elucidate the molecular origin of this long-range coupling, we apply a combination of large-scale molecular simulations and a site-directed mutagenesis experiment of a key residue. In hybrid quantum mechanics/molecular mechanics simulations, we observe that reduction of Q is coupled to its local protonation by the His-38/Asp-139 ion pair and Tyr-87 of subunit Nqo4. Atomistic classical molecular dynamics simulations further suggest that formation of quinol (QH2) triggers rapid dissociation of the anionic Asp-139 toward the membrane domain that couples to conformational changes in a network of conserved charged residues. Site-directed mutagenesis data confirm the importance of Asp-139; upon mutation to asparagine the Q reductase activity is inhibited by 75%. The current results, together with earlier biochemical data, suggest that the proton pumping in complex I is activated by a unique combination of electrostatic and conformational transitions.
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影响因子：
3.3
作者：
Klauda, Jeffery B.;Venable, Richard M.;Freites, J. Alfredo;O'Connor, Joseph W.;Tobias, Douglas J.;Mondragon-Ramirez, Carlos;Vorobyov, Igor;MacKerell, Alexander D., Jr.;Pastor, Richard W.
通讯作者：
Pastor, Richard W.
影响因子：
4.3
作者：
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通讯作者：
Brandt, Ulrich
影响因子：
56.9
作者：
Zickermann, Volker;Wirth, Christophe;Brandt, Ulrich
通讯作者：
Brandt, Ulrich
影响因子：
4.8
作者：
Tocilescu, Maja A.;Fendel, Uta;Brandt, Ulrich
通讯作者：
Brandt, Ulrich
影响因子：
3
作者：
Kieseritzky, Gernot;Knapp, E. W.
通讯作者：
Knapp, E. W.