Prediction of the tertiary structure of the β-secretase zymogen
Prediction of the tertiary structure of the β-secretase zymogen
复制标题
DOI：
10.1006/bbrc.2002.6686
复制
发表时间：
2002-04-05
影响因子：
3.1
通讯作者：
Howe, WJ
中科院分区：
文献类型：
--
作者：
Chou, KC;Howe, WJ
β -分泌酶，也称为BACE，是一种跨膜天冬氨酸蛋白酶，它产生阿尔茨海默病淀粉样β肽的N端。β -分泌酶的活性是体内脑斑块产生的限速步骤，因此是阿尔茨海默病疾病修饰药物的潜在靶标。为了更好地了解β -分泌酶的作用机制，帮助探索阿尔茨海默病药物开发的新策略，阐明β -分泌酶酶原的三维结构是很重要的。基于蛋白酶结构域的x射线结构和胃蛋白酶原的x射线结构，构建了β -分泌酶酶原的三维结构模型。将前bace的计算结构与胃蛋白酶原和前胃泌素（另外两种前天冬氨酸蛋白酶）的x射线结构进行比较，发现前段与催化天冬氨酸的关系存在显著差异。在胃蛋白酶原和前胃泌素中，前段的赖氨酸侧链与两个催化的天冬氨酸形成盐桥，占据通常由催化水占据的位置。在pro-BACE模型中不存在盐桥，相应的残基-a脯氨酸完全不与催化残基相互作用。这些发现可以用来阐明最近的观察结果，即β -分泌酶的前结构域不像严格的酶原那样抑制活性，但似乎有助于活性蛋白酶结构域的适当折叠。预测β -分泌酶酶原的三维结构和相关发现也可能为合理设计抗阿尔茨海默病的有效药物提供有用的见解。(C) 2002 Elsevier Science （USA）。
beta-Secretase, also known as BACE, is a transmembrane aspartyl protease, which generates the N terminus of Alzheimer's disease amyloid beta-peptide. The activity of beta-secretase is the rate-limiting step of brain plaques production in vivo, and hence is a potential target for disease modifying drugs for Alzheimer's disease. To better understand the mechanism of action of beta-secretase and help explore novel strategies for drug discovery for Alzheimer's disease, it is important to elucidate the three-dimensional structure of its zymogen. Based on the X-ray structure of the enzyme's protease domain and the X-ray structure of pepsinogen, a model of the three-dimensional structure of the beta-secretase zymogen has been constructed. Comparison of the computed structure of pro-BACE with X-ray structures of pepsinogen and progastricsin (two other pro-aspartyl proteases) reveals a significant difference in the relationship of the pro-segment to the catalytic aspartates. In both pepsinogen and progastricsin a lysine side-chain in the pro-segment forms a salt bridge to the two catalytic aspartates, occupying the position normally occupied by a catalytic water. In the pro-BACE model there is no salt bridge, and the corresponding residue-a proline does not interact at all with the catalytic residues. These findings can be used to elucidate the recent observations that the pro-domain of beta-secretase does not suppress activity as in a strict zymogen but does appear to facilitate proper folding of an active protease domain. The predicted three-dimensional structure of beta-secretase zymogen and the relevant findings might also provide useful insights for rational design of effective drugs against Alzheimer's disease. (C) 2002 Elsevier Science (USA).