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首页> 外文期刊>Cell cycle >On the interaction mechanisms of a p53 peptide and nutlin with the MDM2 and MDMX proteins: A Brownian dynamics study
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On the interaction mechanisms of a p53 peptide and nutlin with the MDM2 and MDMX proteins: A Brownian dynamics study

机译：关于p53肽和nutlin与MDM2和MDMX蛋白的相互作用机制：布朗动力学研究

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The interaction of p53 with its regulators MDM2 and MDMX plays a major role in regulating the cell cycle. Inhibition of this interaction has become an important therapeutic strategy in oncology. Although MDM2 and MDMX share a very high degree of sequence/ structural similarity, the small-molecule inhibitor nutlin appears to be an efficient inhibitor only of the p53-MDM2 interaction. Here, we investigate the mechanism of interaction of nutlin with these two proteins and contrast it with that of p53 using Brownian dynamics simulations. In contrast to earlier attempts to examine the bound states of the partners, here we locate initial reaction events in these interactions by identifying the regions of space around MDM2/ MDMX, where p53utlin experience associative encounters with prolonged residence times relative to that in bulk solution. We find that the initial interaction of p53 with MDM2 is long-lived relative to nutlin, but, unlike nutlin, it takes place at the N- and C termini of the MDM2 protein, away from the binding site, suggestive of an allosteric mechanism of action. In contrast, nutlin initially interacts with MDM2 directly at the clefts of the binding site. The interaction of nutlin with MDMX, however, is very short-lived compared with MDM2 and does not show such direct initial interactions with the binding site. Comparison of the topology of the electrostatic potentials of MDM2 and MDMX and the locations of the initial encounters with p53utlin in tandem with structure-based sequence alignment revealed that the origin of the diminished activity of nutlin toward MDMX relative to MDM2 may stem partly from the differing topologies of the electrostatic potentials of the two proteins. Glu25 and Lys51 residues underpin these topological differences and appear to collectively play a key role in channelling nutlin directly toward the binding site on the MDM2 surface and are absent in MDMX. The results, therefore, provide new insight into the mechanism of p53utlin interactions with MDM2 and MDMX and could potentially have a broader impact on anticancer drug optimization strategies. ? 2013 Landes Bioscience.
机译：p53与其调节剂MDM2和MDMX的相互作用在调节细胞周期中起主要作用。抑制这种相互作用已成为肿瘤学中的重要治疗策略。尽管MDM2和MDMX具有非常高的序列/结构相似性，但小分子抑制剂nutlin似乎仅是p53-MDM2相互作用的有效抑制剂。在这里，我们研究了nutlin与这两种蛋白质相互作用的机制，并使用布朗动力学模拟将其与p53进行了对比。与先前检查伴侣的结合状态的尝试相反，在这里我们通过识别MDM2 / MDMX周围的空间区域来定位这些相互作用中的初始反应事件，其中p53 / nutlin经历了相对于大量散装的较长停留时间的相遇。解。我们发现p53与MDM2的初始相互作用相对于nutlin而言是长寿的，但是与nutlin不同，它发生在MDM2蛋白的N-和C末端，远离结合位点，暗示了它的变构机制。行动。相反，nutlin最初直接在结合位点的裂口与MDM2相互作用。但是，nutlin与MDMX的相互作用与MDM2相比非常短，并且没有显示出与结合位点的这种直接初始相互作用。 MDM2和MDMX静电势的拓扑结构以及与p53 / nutlin初次相遇的位置与基于结构的序列比对的比较表明，相对于MDM2，nutlin对MDMX活性降低的起源可能部分源于两种蛋白质静电势的不同拓扑。 Glu25和Lys51残基支持这些拓扑差异，并且似乎在将nutlin直接引向MDM2表面的结合位点中起着关键作用，而在MDMX中则不存在。因此，结果为p53 / nutlin与MDM2和MDMX相互作用的机理提供了新的见识，并可能对抗癌药物优化策略产生更广泛的影响。 ？ 2013 Landes生物科学。

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