Structural basis for understanding oncogenic p53 mutations and designing rescue drugs
Structural basis for understanding oncogenic p53 mutations and designing rescue drugs
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DOI：
10.1073/pnas.0607286103
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发表时间：
2006-10-10
影响因子：
11.1
通讯作者：
Fersht, Alan R.
中科院分区：
文献类型：
--
作者：
Joerger, Andreas C.;Ang, Hwee Ching;Fersht, Alan R.
肿瘤抑制因子p53的DNA结合结构域在约50%的人类癌症中因突变而失活。我们已经解决了几种致癌突变体的高分辨率晶体结构，以研究失活的结构基础，并为设计可以拯救失活突变体的药物提供信息。我们发现了突变后的各种结构后果：（i）去除与DNA的基本接触，（ii）产生大的、水可接近的裂缝或疏水性内腔，没有其他结构变化，但热力学稳定性大大丧失，（iii）DNA结合表面的变形，和（iv）不直接参与DNA结合但参与作为四聚体结合时的结构域-结构域相互作用的表面的改变。这些发现解释了功能特性和相关表型的差异（例如，温度敏感性）。一些突变体有可能被一种通用的稳定药物拯救。此外，突变诱导的裂缝是一个潜在的靶位点的mux选择性稳定药物。
The DNA-binding domain of the tumor suppressor p53 is inactivated by mutation in approximate to 50% of human cancers. We have solved high-resolution crystal structures of several oncogenic mutants to investigate the structural basis of inactivation and provide information for designing drugs that may rescue inactivated mutants. We found a variety of structural consequences upon mutation: (i) the removal of an essential contact with DNA, (ii) creation of large, water-accessible crevices or hydrophobic internal cavities with no other structural changes but with a large loss of thermodynamic stability, (iii) distortion of the DNA-binding surface, and (iv) alterations to surfaces not directly involved in DNA binding but involved in domain-domain interactions on binding as a tetramer. These findings explain differences in functional properties and associated phenotypes (e.g., temperature sensitivity). Some mutants have the potential of being rescued by a generic stabilizing drug. In addition, a mutation-induced crevice is a potential target site for a mutant-selective stabilizing drug.