Binding induced folding in p53-MDM2 complex
Binding induced folding in p53-MDM2 complex
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DOI：
10.1021/ja0678774
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发表时间：
2007-03-14
影响因子：
15
通讯作者：
Luo, Ray
中科院分区：
文献类型：
--
作者：
Chen, Hai-Feng;Luo, Ray
MDM2 n端结构域可以结合p53的反激活结构域，下调其激活转录的能力。发现与p53结合可以稳定MDM2 n端结构域。因此，结合和折叠之间的耦合在p53和MDM2之间的正常功能相互作用中是必不可少的。我们对结合的MDM2(N)和载脂蛋白MDM2进行了显式溶剂分子动力学模拟（MD），以研究p53-MDM2复合物中结合和折叠的相互依赖性。高温MD模拟动力学分析表明，结合MDM2N和载子mdm2均通过双态展开。动力学和自由能分析表明，结合MDM2的展开顺序为p53解结合、三级展开、最后二级结构展开。我们的数据表明，结合MDM2N和载脂蛋白mdm2之间的展开途径不同：不稳定螺旋和三级接触的展开顺序相反。跃迁态分析表明，结合MDM2的跃迁态比载脂蛋白MDM2更具有原生性和异质性。预测的Phi值表明，结合MDM2N和载脂蛋白mdm2的稳定螺旋比其他区域更像本地区域。在稳定螺旋内，结合MDM2中的螺旋II比载脂蛋白MDM2中的螺旋II更接近于原生螺旋。然而，结合MDM2中的螺旋I和螺旋IV与载脂蛋白MDM2中的螺旋I和螺旋IV不太相似。
The MDM2 N-terminal domain can bind to the transactivation domain of p53 and downregulate its ability to activate transcription. It was found that binding with p53 stabilizes the MDM2 N-terminal domain. Thus the coupling between binding and folding is essential in the normal functional interactions between p53 and MDM2. We have performed explicit-solvent molecular dynamics simulations (MD) for both bound MDM2(N) and apo-MDM2 to study the interdependence of binding and folding in the p53-MDM2 complex. Kinetic analysis of high-temperature MD simulations shows that both bound MDM2N and apo-MDM2 unfold via a two-state process. Both kinetics and free energy landscape analyses indicate that bound MDM2 unfolds in the order of p53 unbinding, tertiary unfolding, and finally secondary structure unfolding. Our data show that the unfolding pathways are different between bound MDM2N and apo-MDM2: the unfolding order of unstable helices and tertiary contacts is reversed. Transition state analysis shows that the transition state of bound MDM2 is more nativelike and more heterogeneous than that of apo-MDM2. The predicted Phi- values suggest that the stable helices are more nativelike than other regions in both bound MDM2N and apo-MDM2. Within the stable helices, helix II in bound MDM2 is more nativelike than that in apo-MDM2. However, helix I and IV in bound MDM2 are less nativelike than those in apo-MDM2.