文章：

拯救突变型p53的功能

Rescuing the function of mutant p53

原文发布日期：2001-10-01

DOI: 10.1038/35094077

类型: Article

开放获取: 否

要点：

1. Aggressive cancers that do not respond to traditional chemotherapy regimes are often resistant owing to the lack of p53-dependent apoptosis. New therapies are being developed that aim to restore p53 tumour suppression to cancer cells.
2. 50% of cancers lose p53 function as a result of mutations that produce single amino-acid substitutions in the core DNA-binding domain. In other cancers, wild-type p53 is targeted for degradation by cellular (MDM2) or viral (E6) oncoproteins.
3. Mutant p53 is inactive for transcriptional transactivation. Cancer cells therefore accumulate mutant p53 (in the absence of MDM2) and fail to induce p53-dependent growth arrest, DNA repair or apoptosis. The mutant protein is a target for rescue by drugs that bind to the core domain to reverse the effects of mutation.
4. Mutations can reduce the DNA-binding affinity and thermodynamic stability of the core domain to varying extents, described by five mutant classes. The effect of a mutation is largely dictated by its location within the core-domain structure. Mutations in the β-sandwich induce unfolding, whereas mutations in the DNA-binding surface can have a greater effect on DNA binding.
5. The activity of certain p53 mutants can be restored by second-site suppressor mutations that introduce an additional DNA contact, correct local structural distortion or increase the stability of the core domain structure. Potential therapeutic drugs may rescue mutant p53 by the same mechanisms.
6. Small molecules, identified in a screen for protein folding, stabilize the wild-type and mutant p53 core domain, presumably by binding specifically to the native protein. Correction of mutant folding restores p53 function to cancer cells and inhibits tumour growth in mice.
7. These prototype compounds require increased potency for use at concentrations that are practical for cancer therapy. This may be achieved by further structure-based drug design once the binding site on the p53 core domain is characterized. Small molecules have also been discovered that relieve the inhibition of p53 by MDM2 and E6 in cancers that express wild-type p53.

要点翻译：

1. 对传统化疗方案无反应的侵袭性癌症通常因缺乏p53依赖性凋亡而产生耐药性。目前正在开发的新疗法旨在恢复癌细胞的p53肿瘤抑制功能。
2. 50%的癌症因核心DNA结合结构域发生单氨基酸置换突变而丧失p53功能。在其他癌症中，野生型p53被细胞（MDM2）或病毒（E6）癌蛋白靶向降解。
3. 突变型p53失去转录激活活性。因此癌细胞会积累突变型p53（在MDM2缺失情况下），无法诱导p53依赖性生长停滞、DNA修复或凋亡。该突变蛋白可通过药物结合核心结构域来逆转突变效应，成为挽救治疗的靶点。
4. 突变会不同程度降低核心结构域的DNA结合亲和力和热力学稳定性，按影响程度可分为五类突变型。突变效应主要取决于其在核心结构域中的位置：β-折叠区的突变会诱发解折叠，而DNA结合表面的突变对DNA结合能力影响更大。
5. 某些p53突变体的活性可通过第二位点抑制突变恢复，这类突变能引入额外DNA接触、矫正局部结构畸变或增强核心结构域稳定性。潜在治疗药物可能通过相同机制挽救突变型p53。
6. 在蛋白质折叠筛选中发现的小分子化合物能特异性结合天然蛋白，从而稳定野生型和突变型p53核心结构域。矫正突变蛋白折叠可恢复癌细胞的p53功能并抑制小鼠肿瘤生长。
7. 这些原型化合物需提高效价才能达到癌症治疗所需的实用浓度。一旦明确p53核心结构域的结合位点，通过进一步基于结构的药物设计可实现该目标。此外还发现了能解除MDM2和E6对野生型p53抑制的小分子化合物。

英文摘要：

One protein — p53 — plays nemesis to most cancers by condemning damaged cells to death or quarantining them for repair. But the activity of p53 relies on its intact native conformation, which can be lost following mutation of a single nucleotide. With thousands of such mutations identified in patients, how can a future cancer drug buttress this fragile protein structure and restore the cell's natural defence?

摘要翻译： 

一种名为p53的蛋白质通过促使受损细胞死亡或隔离修复来对抗大多数癌症。但p53的活性依赖于其完整的天然构象，这种构象可能因单个核苷酸突变而丧失。在患者身上已发现数千种此类突变的情况下，未来的癌症药物如何支撑这一脆弱的蛋白质结构并恢复细胞的天然防御能力？

原文链接：

Rescuing the function of mutant p53