Differential binding of p53 and nutlin to MDM2 and MDMX Computational studies
Differential binding of p53 and nutlin to MDM2 and MDMX Computational studies
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DOI：
10.4161/cc.9.6.11067
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发表时间：
2010-03-15
期刊：
影响因子：
4.3
通讯作者：
Verma, Chandra
中科院分区：
文献类型：
--
作者：
Joseph, Thomas Leonard;Madhumalar, Arumugam;Verma, Chandra
一半的人类肿瘤已经突变了p53，而在另一半中，有缺陷的信号通路阻止了它的功能。其中一个缺陷是MDM2和MDMX蛋白的过度表达。这导致了大力开发P53-MDM2/MDMX相互作用的抑制剂。Nutlin是第一个被描述为阻止p53-MDM2相互作用的化合物。分子动力学模拟已经被用来探索p53和Nutlin与MDM2/MDMX结合的差异。模拟表明，在更强的静电相互作用的推动下，p53对MDM2的亲和力比MDMX更高。P53被Nutlin取代了MDM2，因为它更灵活，因此在MDM2的封存时支付了更大的熵惩罚。MDM2的固有可塑性高于MDMX，使其能够同时结合P53和Nutlin。不太灵活的MDMX与更具流动性的P53相互作用，因为多肽可以从构象上适应对接到MDMX中，尽管亲和力降低；然而，Nutlin是刚性的，因此只能与低亲和力的MDMX相互作用。在进化上，MDM2对P53的高亲和力可能使MDM2在将P53送出细胞核时，能够与P53结合更长时间；相反，MDMX只需要掩蔽P53的TA结构域。这项研究使我们能够假设功能突变或那些降低了对Nutlin亲和力的突变的获得。这些结论为MDM2和MDMX双重抑制剂的未来药物设计提供了洞察力，这两种药物都是在许多癌症中发现过度表达的癌蛋白。
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.