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首页> 外文期刊>Cell cycle >Differential binding of p53 and nutlin to MDM2 and MDMX: Computational studies.
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Differential binding of p53 and nutlin to MDM2 and MDMX: Computational studies.

机译：p53和nutlin与MDM2和MDMX的差异结合：计算研究。

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Half of human tumours have mutated p53 while in the other half, defective signalling pathways block its function. One such defect is the overexpression of the MDM2 and MDMX proteins. This has led to an intense effort to develop inhibitors of p53-MDM2/MDMX interactions. Nutlin is the first such compound described to block p53-MDM2 interactions. Molecular dynamics simulations have been used to explore the differences in binding of p53 and nutlin to MDM2/MDMX. Simulations reveal that p53 has a higher affinity for MDM2 than MDMX, driven by stronger electrostatic interactions. p53 is displaced from MDM2 by nutlin because it is more flexible, thus paying a larger entropic penalty upon sequestration by MDM2. The inherent plasticity of MDM2 is higher than that of MDMX, enabling it to bind both p53 and nutlin. The less flexible MDMX interacts with the more mobile p53 because the peptide can adapt conformationally to dock into MDMX, albeit with a reduced affinity; nutlin, however is rigid and hence can only interact with MDMX with low affinity. Evolutionarily, the higher affinity of MDM2 for p53 may enable MDM2 to bind p53 for longer periods as it shuttles it out of the nucleus; in contrast, MDMX only needs to mask the p53 TA domain. This study enables us to hypothesize gain of function mutations or those that have decreased affinity for nutlin. These conclusions provide insight into future drug design for dual inhibitors of MDM2 and MDMX, both of which are oncoproteins found overexpressed in many cancers.
机译：人类肿瘤的一半已经突变了p53，而另一半则有缺陷的信号传导通路阻断了其功能。一种这样的缺陷是MDM2和MDMX蛋白的过表达。这导致开发p53-MDM2 / MDMX相互作用抑制剂的努力。 Nutlin是第一个描述的可阻断p53-MDM2相互作用的化合物。分子动力学模拟已用于探索p53和nutlin与MDM2 / MDMX结合的差异。模拟表明，p53对MDM2的亲和力比MDMX高，这是由于较强的静电相互作用所致。 p53被Nutlin取代，是因为它具有更大的灵活性，因此被Mutlin取代了，因此在MDM2螯合时付出了更大的熵代价。 MDM2的固有可塑性高于MDMX，从而使其能够结合p53和nutlin。柔韧性较差的MDMX与流动性更高的p53相互作用，因为该肽虽然在亲和力方面有所降低，但仍可以在构象上适应停靠入MDMX。但是，nutlin是刚性的，因此只能以低亲和力与MDMX相互作用。从进化上看，MDM2对p53的亲和力更高，可以使MDM2在更长的时间内将p53转运出核，从而与p53结合。相比之下，MDMX只需要掩盖p53 TA域。这项研究使我们能够假设功能突变的获得或对nutlin亲和力降低的突变。这些结论为MDM2和MDMX的双重抑制剂的未来药物设计提供了见识，这两种抑制剂都是在许多癌症中过表达的癌蛋白。

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