Impact of low-frequency hotspot mutation R282Q on the structure of p53 DNA-binding domain as revealed by crystallography at 1.54 angstroms resolution.
Impact of low-frequency hotspot mutation R282Q on the structure of p53 DNA-binding domain as revealed by crystallography at 1.54 angstroms resolution.
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通过晶体学以 1.54 埃分辨率揭示低频热点突变 R282Q 对 p53 DNA 结合域结构的影响。
DOI：
10.1107/s0907444908003338
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发表时间：
2008
期刊：
影响因子：
--
通讯作者：
Ji,Xinhua
中科院分区：
文献类型：
--
作者：
Tu,Chao;Tan,YuHong;Shaw,Gary;Zhou,Zheng;Bai,Yawen;Luo,Ray;Ji,Xinhua
抑癌基因p53是一种序列特异性DNA结合蛋白，其中心DNA结合域（DBD）含有6个肿瘤热点（Arg175，Gly245，Arg248，Arg249，Arg273和Arg282）。在这里，晶体结构的低频热点突变体，p53 DBD（R282Q），报告在1.54 μ m分辨率与分子动力学模拟的结果的基础上的结构。 除了消除盐桥之外，R282Q突变对两个DNA结合环（L1和L3）的性质具有显著影响。L1环在野生型中是柔性的，但在突变体中是不柔性的。野生型的L3环是不灵活的，而它在突变体中呈现两种构象。分子动力学模拟表明，这两种构象的L3环在生物条件下是可访问的。据预测，盐桥的消除和L1和L3的柔性的反转直接或间接地导致肿瘤抑制因子p53失活。
Tumor suppressor p53 is a sequence-specific DNA-binding protein and its central DNA-binding domain (DBD) harbors six hotspots (Arg175, Gly245, Arg248, Arg249, Arg273 and Arg282) for human cancers. Here, the crystal structure of a low-frequency hotspot mutant, p53DBD(R282Q), is reported at 1.54 Å resolution together with the results of molecular-dynamics simulations on the basis of the structure. In addition to eliminating a salt bridge, the R282Q mutation has a significant impact on the properties of two DNA-binding loops (L1 and L3). The L1 loop is flexible in the wild type, but it is not flexible in the mutant. The L3 loop of the wild type is not flexible, whereas it assumes two conformations in the mutant. Molecular-dynamics simulations indicated that both conformations of the L3 loop are accessible under biological conditions. It is predicted that the elimination of the salt bridge and the inversion of the flexibility of L1 and L3 are directly or indirectly responsible for deactivating the tumor suppressor p53.