CRYSTAL-STRUCTURE OF A P53 TUMOR-SUPPRESSOR DNA COMPLEX - UNDERSTANDING TUMORIGENIC MUTATIONS
CRYSTAL-STRUCTURE OF A P53 TUMOR-SUPPRESSOR DNA COMPLEX - UNDERSTANDING TUMORIGENIC MUTATIONS
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DOI：
10.1126/science.8023157
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发表时间：
1994-07-15
期刊：
影响因子：
56.9
通讯作者：
PAVLETICH, NP
中科院分区：
文献类型：
--
作者：
CHO, YJ;GORINA, S;PAVLETICH, NP
p53肿瘤抑制基因突变是人类癌症中最常见的遗传改变。大多数突变发生在含有p53蛋白的序列特异性DNA结合活性的核心结构域（残基102-292）中，并且它们导致DNA结合的丧失。含有人p53的核心结构域和DNA结合位点的复合物的晶体结构已被确定为2.2埃的分辨率，并细化到20.5%的晶体学R因子。核心结构域结构由β夹心结构组成，该β夹心结构用作两个大环和环-片-螺旋基序的支架。这两个环部分地通过四面体配位的锌原子保持在一起，并且环-片-螺旋基序形成p53的DNA结合表面。来自环-片-螺旋基序的残基在DNA的大沟中相互作用，而来自两个大环之一的精氨酸在小沟中相互作用。环和环-片-螺旋基序由核心结构域的保守区域组成，并含有肿瘤中鉴定的大多数p53突变。该结构支持DNA结合对p53的生物活性至关重要的假设，并为理解突变如何抑制p53提供了框架。
Mutations in the p53 tumor suppressor are the most frequently observed genetic alterations in human cancer. The majority of the mutations occur in the core domain which contains the sequence-specific DNA binding activity of the p53 protein (residues 102-292), and they result in loss of DNA binding. The crystal structure of a complex containing the core domain of human p53 and a DNA binding site has been determined at 2.2 angstroms resolution and refined to a crystallographic R factor of 20.5 percent. The core domain structure consists of a beta sandwich that serves as a scaffold for two large loops and a loop-sheet-helix motif. The two loops, which are held together in part by a tetrahedrally coordinated zinc atom, and the loop-sheet-helix motif form the DNA binding surface of p53. Residues from the loop-sheet-helix motif interact in the major groove of the DNA, while an arginine from one of the two large loops interacts in the minor groove. The loops and the loop-sheet-helix motif consist of the conserved regions of the core domain and contain the majority of the p53 mutations identified in tumors. The structure supports the hypothesis that DNA binding is critical for the biological activity of p53, and provides a framework for understanding how mutations inactivate it.