Quantitative analysis of residual folding and DNA binding in mutant p53 core domain: definition of mutant states for rescue in cancer therapy
Quantitative analysis of residual folding and DNA binding in mutant p53 core domain: definition of mutant states for rescue in cancer therapy
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DOI：
10.1038/sj.onc.1203434
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发表时间：
2000-03-02
期刊：
影响因子：
8
通讯作者：
Fersht, AR
中科院分区：
文献类型：
--
作者：
Bullock, AN;Henckel, J;Fersht, AR
肿瘤抑制基因p53在一半的人类癌症中发生突变，最常见的是其核心区存在错义替换。我们基于对分离的核心区的定量折叠和DNA结合研究，对突变数据库进行了新的评估。我们的数据确定了五个不同的突变类，这些突变类与核心域结构的四个明确定义的区域相关。在外推到37摄氏度时，野生型蛋白的稳定性为3.0千卡/摩尔，这也是一个致癌阈值：所有不稳定到这个量(50%变性)的β-三明治突变体预计都会促进癌症。其他弱不稳定突变被限制在DNA结合区的环3，稳定突变P53折叠的药物有可能通过反式激活依赖或独立的途径重新激活肿瘤细胞中的凋亡信号通路。利用亲和配体作为原理证明，我们恢复了热点G245S的热力学稳定性。以五个突变类别的参考状态为指导，未来的治疗策略可能类似地稳定突变P53的部分结构或结合状态，从而恢复有限的P53抑制肿瘤的途径。
The tumour suppressor p53 is mutated in half of all human cancers, most frequently with missense substitutions in its core domain. We present a new assessment of the mutation database based on quantitative folding and DNA-binding studies of the isolated core domain. Our data identify five distinct mutant classes that correlate with four well-defined regions of the core domain structure. On extrapolation to 37 degrees C the wild-type protein has a stability of 3.0 kcal/mol, This also emerges as an oncogenic threshold: all beta-sandwich mutants destabilized by this amount (50% denatured) are expected to promote cancer. Other weakly destabilizing mutations are restricted to loop 3 in the DNA-binding region, Drugs that stabilize mutant p53 folding have the potential to reactivate apoptotic signalling pathways in tumour cells either by transactivation-dependent or independent pathways. Using an affinity ligand as a proof of principle we have recovered the thermodynamic stability of the hotspot G245S. With reference states for the five mutant classes as a guide, future therapeutic strategies may similarly stabilize partially structured or binding states of mutant p53 that restore limited p53 pathways to tumour suppression.