Predicted three-dimensional structure of the protease inhibitor domain of the Alzheimer's disease beta-amyloid precursor.
Predicted three-dimensional structure of the protease inhibitor domain of the Alzheimer's disease beta-amyloid precursor.
复制标题
阿尔茨海默病β-淀粉样蛋白前体的蛋白酶抑制剂结构域的预测三维结构。
DOI：
10.1002/prot.340090102
复制
发表时间：
1991
期刊：
影响因子：
2.9
通讯作者：
Hagler,AT
中科院分区：
文献类型：
--
作者：
Struthers,RS;Kitson,DH;Hagler,AT
阿尔茨海默病的特征是β-淀粉样蛋白在患者大脑中以斑块和缠结的形式沉积。淀粉样蛋白前体可以在包含或不包含蛋白酶抑制剂结构域的情况下表达，其在淀粉样蛋白生成中的潜在作用促使基于相关抑制剂的已知结构生成其三维结构模型。模型结构预测突变残基几乎完全位于抑制剂结构域的表面，而保守残基构成疏水核心。此外，还发现了几对结构互补或一致的突变。这些结构特征为建模结构的有效性提供了强有力的证据，并且建议除了突变的（空间）位置之外，互补突变的存在可以用作评估同源性构建的蛋白质结构的标准。界定结构域的末端残基是距离蛋白酶结合位点最远的残基，并且彼此非常接近，因此表明该结构域能够在较大蛋白质的背景下充当结构盒。该抑制剂和相关牛胰腺胰蛋白酶抑制剂的静电势揭示了两种净电荷截然不同的抑制剂如何以大致相同的结合常数与胰蛋白酶结合，并表明胰蛋白酶的突变可能选择性增强淀粉样蛋白抑制剂结构域的结合。该模型为理解该结构域中残基的功能作用以及设计更简单的分子来测试作为干预阿尔茨海默病的药物提供了结构基础。
Alzheimer's disease is characterized by the deposition of amyloid β‐protein as plaques and tangles in the brains of its victims. The amyloid precursor can be expressed with or without the inclusion of a protease inhibitor domain, the potential role of which in amyloidogenesis has prompted the generation of a model of its three‐dimensional structure based on the known structure of a related inhibitor. The model structure predicts that the mutated residues are almost entirely on the surface of the inhibitor domain, while conserved residues constitute the hydrophobic core. In addition, several pairs of structurally complementary, or concerted, mutations are seen. These structural features provide strong evidence for the validity of the modeled structure, and it is suggested that the presence of complementary mutations may be used as a criterion for evaluating protein structures built by homology, in addition to the (spatial) location of the mutations. The terminal residues delimiting the domain are among those furthest from the protease binding site and are in close proximity to one another, thus suggesting the ability of the domain to function as a structural cassette within the context of a larger protein. The electrostatic potentials of the inhibitor and of the related bovine pancreatic trypsin inhibitor reveal how two inhibitors with very different net charges can bind with approximately the same binding constant to trypsin and suggest a mutation of trypsin that might selectively enhance the binding of the amyloid inhibitor domain. The model provides a structural basis for understanding the functional roles of residues in the domain and for designing simpler molecules to test as pharmacologic agents for intervention in Alzheimer's disease.