Bioinformatics Institute (A-STAR), Matrix, Singapore.
Cell Cycle. 2010 Mar 15;9(6):1167-81. doi: 10.4161/cc.9.6.11067.
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.
一半的人类肿瘤中 p53 发生了突变，而在另一半肿瘤中，缺陷的信号通路会阻断其功能。其中一个缺陷是 MDM2 和 MDMX 蛋白的过表达。这导致了开发 p53-MDM2/MDMX 相互作用抑制剂的巨大努力。Nutlin 是第一种被描述为阻断 p53-MDM2 相互作用的化合物。分子动力学模拟已被用于探索 p53 和 Nutlin 与 MDM2/MDMX 结合的差异。模拟结果表明，p53 与 MDM2 的结合亲和力高于 MDMX，这是由更强的静电相互作用驱动的。Nutlin 将 p53 从 MDM2 中置换出来，因为它更灵活，因此在被 MDM2 隔离时会产生更大的熵损失。MDM2 的固有可塑性高于 MDMX，使其能够结合 p53 和 Nutlin。柔韧性较低的 MDMX 与更具移动性的 p53 相互作用，因为该肽可以通过构象适应与 MDMX 对接，尽管亲和力降低；然而，Nutlin 是刚性的，因此只能与 MDMX 以低亲和力相互作用。从进化的角度来看，MDM2 对 p53 的更高亲和力可能使其能够在核外将其转运出核的更长时间内与 p53 结合；相比之下，MDMX 只需要掩盖 p53 TA 结构域。这项研究使我们能够假设获得功能突变或那些对 Nutlin 的亲和力降低的突变。这些结论为设计针对 MDM2 和 MDMX 的双重抑制剂提供了启示，这两种蛋白都是在许多癌症中过度表达的致癌蛋白。
