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Mechanism of the Translation Termination Reaction on the Ribosome

机译：核糖体翻译终止反应的机理

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摘要

Ribosomal release factors (RFs) catalyze the termination of protein synthesis by triggeringnhydrolysis of the peptidyl-tRNA ester bond in the peptidyl transferase center of the ribosome. With newnmedium-resolution crystallographic structures of RF-ribosome complexes available, it has become possiblento examine the detailed mechanism of this process to resolve the key factors responsible for catalysis ofnthe termination reaction. Here, we report computer simulations of the termination reaction that utilize bothnthe new RF complex structures and information from a high-resolution complex with a P-site substratenanalogue. The calculations yield a consistent reaction mechanism that reproduces experimental rates andnallows us to identify key interactions responsible for the catalytic efficiency. The results are also in generalnagreement with an earlier model based on molecular docking. The methylated glutamine residue of thenuniversally conservedGGQmotif plays a key role in the hydrolysis reaction by orienting thewater nucleophilenand by stabilizing the transition state, and its side chain makes an entropic contribution to the lowering of thenactivation barrier. Two additional water molecules interacting with the P-site substrate are also found to bencritically important. Furthermore, the 20n-OH group of the peptidyl-tRNA substrate is predicted to act as anproton shuttle for the leaving group in analogy with the consensus mechanism for peptidyl transfer. Thus, thenribosome’s ability to catalyze both the termination (hydrolysis) and peptidyl transfer (aminolysis) reactions isnlargely explained by this type of unifiedmechanism, with similar transition states occurring in both processes.
机译：核糖体释放因子（RFs）通过触发核糖体肽基转移酶中心的肽基-tRNA酯键的水解来催化蛋白质合成的终止。有了可用的RF核糖体复合物的新的纳米级分辨晶体学结构，就有可能研究该过程的详细机理，以解决负责催化终止反应的关键因素。在这里，我们报告了利用新的RF复合物结构和来自具有P位置底物类似物的高分辨率复合物的信息进行的终止反应的计算机模拟。该计算产生了一致的反应机理，该机理再现了实验速率，并且使我们无法识别造成催化效率的关键相互作用。结果也与基于分子对接的早期模型基本一致。通用保守的GGQmotif的甲基化谷氨酰胺残基通过稳定过渡态使水亲核体取向，从而在水解反应中起关键作用，并且其侧链对降低随后的活化势垒起到了熵的作用。还发现另外两个与P位底物相互作用的水分子极其重要。此外，类似于肽基转移的共有机制，肽基-tRNA底物的20n-OH基团预计将充当离去基团的质子穿梭。因此，核糖体既能催化终止（水解）反应又能催化肽基转移（氨解反应）的能力，在很大程度上由这种类型的统一机制来解释，在两个过程中都发生了类似的过渡态。

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  • 来源
    《Biochemistry》 |2009年第47期|p.11296-11303|共8页
  • 作者

    Stefan Trobro and Johan Aqvist;

  • 作者单位

    Department of Cell and Molecular Biology, Uppsala University, Biomedical Center, Box 596, SE-751 24 Uppsala, Sweden;

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