Coupling between catalytic loop motions and enzyme global dynamics.
Coupling between catalytic loop motions and enzyme global dynamics.
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催化环运动与酶全球动力学之间的耦合。
DOI：
10.1371/journal.pcbi.1002705
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发表时间：
2012
影响因子：
4.3
通讯作者：
Doruker P
中科院分区：
文献类型：
--
作者：
Kurkcuoglu Z;Bakan A;Kocaman D;Bahar I;Doruker P
在许多酶中，催化环运动有助于底物识别和结合。虽然这些运动看起来非常灵活，但它们的功能意义表明，结构编码的偏好可能在选择特定的运动机制方面发挥作用。我们对一组酶进行了广泛的研究，以评估弹性网络模型(ENM)预测的集体/全局动力学是否促进甚至定义了功能环经历的局部运动。我们的数据集包括十种不同大小和齐聚状态的酶的总共117个晶体结构。每种酶都包含一个特定的功能/催化环(10-21个残基长)，在催化过程中关闭活性部位。主成分分析(PCA)的晶体结构(包括载脂蛋白和配体结合形式)揭示了这些环在底物结合时发生的主要构象变化。这些实验观察到的环重新配置被证明主要是由能量上受青睐的运动模式驱动的，这种运动模式在没有底物的情况下是酶固有的。分析表明，由整体酶结构协同定义的健壮的全局模式也需要帮助活性部位上的催化环适当打开/关闭的局部组件。蛋白质环在配体结合和催化中起着关键作用。在这种情况下，一个悬而未决的问题是，蛋白质的内在动力学在多大程度上预先配置了环来执行其分子功能。在这项工作中，我们(I)基于一组酶晶体结构，在存在/不存在配体的情况下，批判性地检查功能/催化环所经历的结构变化，(Ii)检查这些运动在多大程度上与使用简化的基于物理的模型可预测的全局模式相关或受其驱动。使用10种不同大小和寡聚化状态的酶的117个结构的数据集，我们表明由蛋白质拓扑定义的集体模式有利于环重排，与激活时实验观察到的结果合理一致。这些结果表明，整个结构编码的简单但健壮的运动，而不仅仅是局部结合部位，有助于配体的结合、催化环的定位和/或催化部位的隔离，这反过来又使有效的催化成为可能。
Catalytic loop motions facilitate substrate recognition and binding in many enzymes. While these motions appear to be highly flexible, their functional significance suggests that structure-encoded preferences may play a role in selecting particular mechanisms of motions. We performed an extensive study on a set of enzymes to assess whether the collective/global dynamics, as predicted by elastic network models (ENMs), facilitates or even defines the local motions undergone by functional loops. Our dataset includes a total of 117 crystal structures for ten enzymes of different sizes and oligomerization states. Each enzyme contains a specific functional/catalytic loop (10–21 residues long) that closes over the active site during catalysis. Principal component analysis (PCA) of the available crystal structures (including apo and ligand-bound forms) for each enzyme revealed the dominant conformational changes taking place in these loops upon substrate binding. These experimentally observed loop reconfigurations are shown to be predominantly driven by energetically favored modes of motion intrinsically accessible to the enzyme in the absence of its substrate. The analysis suggests that robust global modes cooperatively defined by the overall enzyme architecture also entail local components that assist in suitable opening/closure of the catalytic loop over the active site. Protein loops have critical roles in ligand binding and catalysis. An unresolved issue in this context is the extent to which the intrinsic dynamics of proteins predispose loops to perform their molecular function. In this work, we (i) critically examine the structural changes undergone by functional/catalytic loops based on a set of enzyme crystal structures in the presence/absence of a ligand, and (ii) examine to what extent those motions are correlated with, or driven by, the global modes that are predictable using simplified, physics-based models. Using a dataset of 117 structures for ten enzymes of different sizes and oligomerization states, we show that the collective modes defined by the protein topology favor loop rearrangements in reasonable agreement with those experimentally observed upon activation. These results suggest that simple but robust motions encoded by the entire architecture, not the local binding site only, assist in binding of the ligand, positioning of the catalytic loop, and/or sequestration of the catalytic site, which in turn, enable efficient catalysis.
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DOI：
10.1126/science.1198542
发表时间：
2011-04-08
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Bhabha G;Lee J;Ekiert DC;Gam J;Wilson IA;Dyson HJ;Benkovic SJ;Wright PE
通讯作者：
Wright PE
影响因子：
2.9
作者：
Juszczak, LJ;Zhang, ZY;Eads, DD
通讯作者：
Eads, DD
DOI：
10.1016/j.bbrc.2006.04.181
发表时间：
2006-07-07
影响因子：
3.1
作者：
Kamerlin, Shina Caroline Lynn;Rucker, Robert;Boresch, Stefan
通讯作者：
Boresch, Stefan
影响因子：
3
作者：
Duan, Y;Wu, C;Kollman, P
通讯作者：
Kollman, P
影响因子：
3
作者：
BROOKS, BR;BRUCCOLERI, RE;KARPLUS, M
通讯作者：
KARPLUS, M