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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Stability And Structural Recovery Of The Tetramerization Domain Of P53-r337h Mutant Induced By A Designed Templating Ligand
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Stability And Structural Recovery Of The Tetramerization Domain Of P53-r337h Mutant Induced By A Designed Templating Ligand

机译：设计模板配体诱导的P53-r337h突变体四聚域的稳定性和结构恢复

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摘要

Protein p53 is a transcription factor crucial for cell cycle and genome integrity. It is able to induce both cell arrest when DNA is damaged and the expression of DNA repair machinery. When the damage is irreversible, it triggers apoptosis. Indeed, the protein, which is a homotetramer, is mutated in most human cancers. For instance, the inherited mutation p53-R337H results in destabilization of the tet-ramer and, consequently, leads to an organism prone to tumor setup. We describe herein a rational designed molecule capable of holding together the four monomers of the mutated p53-R337H protein, recovering the tetramer integrity as in the wild-type structure. Two ligand molecules, based on a conical calix[4]arene with four cationic guanidiniomethyl groups at the wider edge (upper rim) and hydro-phobic loops at the narrower edge (lower rim), fit nicely and cooperatively into the hydrophobic clefts between two of the monomers at each side of the protein and keep the tetrameric structure, like molecular templates, by both ion-pair and hydrophobic interactions. We found a good agreement between the structure of the complex and the nature of the interactions involved by a combination of theory (molecular dynamics) and experiments (circular dichroism, differential scanning calorimetry and ~1H saturation transfer difference NMR).
机译：p53蛋白是对细胞周期和基因组完整性至关重要的转录因子。它能够诱导DNA受损时的细胞停滞和DNA修复机制的表达。当损害是不可逆的时，它会引发细胞凋亡。实际上，这种蛋白质是同源四聚体，在大多数人类癌症中都发生了突变。例如，遗传的突变p53-R337H导致tet-ramer的不稳定，并因此导致易于发生肿瘤的生物体。我们在本文中描述了一种合理设计的分子，该分子能够将突变的p53-R337H蛋白的四个单体结合在一起，恢复野生型结构中的四聚体完整性。两个基于圆锥杯[4]芳烃的配体分子在较宽的边缘（上边缘）具有四个阳离子胍基碘甲基，在较窄的边缘（下边缘）具有疏水环，可以很好地配合进入两个分子之间的疏水缝隙中通过离子对和疏水相互作用，使蛋白质两面的单体保持一致，并保持四聚体结构（如分子模板）。我们通过理论（分子动力学）和实验（圆二色性，差示扫描量热法和〜1H饱和转移差分NMR）的结合发现了配合物的结构与相互作用的性质之间的良好一致性。

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