Crystal structures at 2.2 A resolution of the catalytic domains of normal ras protein and an oncogenic mutant complexed with GDP.
Crystal structures at 2.2 A resolution of the catalytic domains of normal ras protein and an oncogenic mutant complexed with GDP.
复制标题
2.2 晶体结构 正常 ras 蛋白和与 GDP 复合的致癌突变体的催化结构域的分辨率。
DOI：
10.1016/0022-2836(91)90753-s
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发表时间：
1991
影响因子：
5.6
通讯作者：
Kim,SH
中科院分区：
文献类型：
--
作者：
Tong,LA;deVos,AM;Milburn,MV;Kim,SH
ras蛋白的生物学功能由结合的鸟嘌呤核苷酸GDP或GTP控制。 GTP 结合构象具有生物活性，并通过与 GAP（GTP 酶激活蛋白）相互作用迅速失活为 GDP 结合构象。大多数ras蛋白的转化突变体即使在GAP存在的情况下也大大降低了GTP水解速率。 Ras 蛋白 GDP 复合物的晶体结构以 2.2 Å 分辨率揭示了 theras 蛋白与 GDP 分子之间详细的相互作用。所有目前已知的转化突变位置都聚集在结合的鸟嘌呤核苷酸分子周围。假定的“效应器”区域和 GAP 识别区域都高度暴露。除了缬氨酸残基的侧链外，正常拉斯蛋白的 GDP 复合物与第 12 位具有缬氨酸的致癌突变体之间没有发现显着的结构差异。然而，与ras蛋白的GTP类似物复合物的比较表明，缬氨酸侧链可能以两种可能的方式抑制GTP水解：（1）直接与γ-磷酸相互作用并改变其方向或磷酸周围的蛋白质残基的构象；和/或(2)防止GTP水解时γ-磷酸盐的离开或亲核基团的进入以攻击γ-磷酸盐。 ras蛋白和细菌延伸因子Tu之间的结构相似性表明它们的共同结构基序对于其他鸟嘌呤核苷酸结合蛋白可能是保守的。
The biological functions ofrasproteins are controlled by the bound guanine nucleotide GDP or GTP. The GTP-bound conformation is biologically active, and is rapidly deactivated to the GDP-bound conformation through interaction with GAP (GTPase Activating Protein). Most transforming mutants ofrasproteins have drastically reduced GTP hydrolysis rates even in the presence of GAP. The crystal structures of the GDP complexes ofrasproteins at 2.2 Å resolution reveal the detailed interaction between therasproteins and the GDP molecule. All the currently known transforming mutation positions are clustered around the bound guanine nucleotide molecule. The presumed “effector” region and the GAP recognition region are both highly exposed. No significant structural differences were found between the GDP complexes of normalrasprotein and the oncogenic mutant with valine at position 12, except the side-chain of the valine residue. However, comparison with GTP-analog complexes ofrasproteins suggests that the valine side-chain may inhibit GTP hydrolysis in two possible ways: (1) interacting directly with the γ-phosphate and altering its orientation or the conformation of protein residues around the phosphates; and/or (2) preventing either the departure of γ-phosphate on GTP hydrolysis or the entrance of a nucleophilic group to attack the γ-phosphate. The structural similarity betweenrasprotein and the bacterial elongation factor Tu suggests that their common structural motif might be conserved for other guanine nucleotide binding proteins.