Simulating molecular mechanisms of the MDM2-mediated regulatory interactions: a conformational selection model of the MDM2 lid dynamics.
Simulating molecular mechanisms of the MDM2-mediated regulatory interactions: a conformational selection model of the MDM2 lid dynamics.
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DOI：
10.1371/journal.pone.0040897
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Verkhivker GM
中科院分区：
文献类型：
--
作者：
Verkhivker GM
MDM 2机制的多样性和复杂性决定了其作为p53肿瘤抑制因子的细胞拮抗剂的主要功能。结构和生物物理学研究表明，MDM 2结合可以通过假底物盖基序的动力学来调节。然而，这些实验和随后的计算研究产生了MDM 2功能和动力学的相互冲突的机制模型。我们提出了一个统一的构象选择模型，可以调和实验结果，并揭示了一个基本的作用的盖子作为一个动态调节MDM 2介导的结合。在这项工作中，apo-MDM 2的结构，动力学和能量学的翻译后修饰和盖子的长度的函数进行了研究。我们发现，“封闭”和“半封闭”盖形式之间的动态平衡可能是MDM 2调节相互作用的基本特征，其可以通过磷酸化、磷酸化模拟突变以及盖大小来调节。我们的研究结果表明，这些因素可能会调节p53-MDM 2的结合微调之间的热力学平衡预先存在的构象状态的apo-MDM 2。与NMR研究一致，磷酸化对MDM 2相互作用的影响在截短的盖子变体中更明显，该变体有利于显性封闭形式。拟磷酸化突变S17 D可能会改变盖动力学的热力学平衡朝着合奏的“半封闭”构象。在具有完整盖子的模拟中看到的占主导地位的“半封闭”盖子形式和对磷酸化的减弱依赖性可以为基于小p53的模拟物和抑制剂的结合提供理论基础，而不与盖子动力学直接竞争。结果表明，预先存在的MDM 2状态的构象选择模型可以为理解MDM 2动力学提供一个强大的理论框架。探索MDM 2调控的生物学功能和机制需要进一步整合计算和实验研究，并可能有助于指导新型抗癌治疗药物的设计。
Diversity and complexity of MDM2 mechanisms govern its principal function as the cellular antagonist of the p53 tumor suppressor. Structural and biophysical studies have demonstrated that MDM2 binding could be regulated by the dynamics of a pseudo-substrate lid motif. However, these experiments and subsequent computational studies have produced conflicting mechanistic models of MDM2 function and dynamics. We propose a unifying conformational selection model that can reconcile experimental findings and reveal a fundamental role of the lid as a dynamic regulator of MDM2-mediated binding. In this work, structure, dynamics and energetics of apo-MDM2 are studied as a function of posttranslational modifications and length of the lid. We found that the dynamic equilibrium between “closed” and “semi-closed” lid forms may be a fundamental characteristic of MDM2 regulatory interactions, which can be modulated by phosphorylation, phosphomimetic mutation as well as by the lid size. Our results revealed that these factors may regulate p53-MDM2 binding by fine-tuning the thermodynamic equilibrium between preexisting conformational states of apo-MDM2. In agreement with NMR studies, the effect of phosphorylation on MDM2 interactions was more pronounced with the truncated lid variant that favored the thermodynamically dominant closed form. The phosphomimetic mutation S17D may alter the lid dynamics by shifting the thermodynamic equilibrium towards the ensemble of “semi-closed” conformations. The dominant “semi-closed” lid form and weakened dependence on the phosphorylation seen in simulations with the complete lid can provide a rationale for binding of small p53-based mimetics and inhibitors without a direct competition with the lid dynamics. The results suggested that a conformational selection model of preexisting MDM2 states may provide a robust theoretical framework for understanding MDM2 dynamics. Probing biological functions and mechanisms of MDM2 regulation would require further integration of computational and experimental studies and may help to guide drug design of novel anti-cancer therapeutics.
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影响因子：
2.8
作者：
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通讯作者：
VANGUNSTEREN, WF
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影响因子：
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作者：
Chen J;Zhang D;Zhang Y;Li G
通讯作者：
Li G
影响因子：
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Brown CJ;Dastidar SG;Quah ST;Lim A;Chia B;Verma CS
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