Functional plasticity in the substrate binding site of β-secretase
Functional plasticity in the substrate binding site of β-secretase
复制标题
DOI：
10.1016/j.str.2005.06.015
复制
发表时间：
2005-10-01
期刊：
影响因子：
5.7
通讯作者：
Caflisch, A
中科院分区：
文献类型：
--
作者：
Gorfe, AA;Caflisch, A
天冬氨酸蛋白酶β-分泌酶（BACE）将淀粉样前体蛋白切割成42个残基的β-肽，其是阿尔茨海默病的主要生化标志物。多个显式水分子动力学模拟的载脂蛋白和抑制剂结合结构的BACE表明，开放和封闭的皮瓣构象是在室温下访问，并应考虑到抑制剂的设计。相关的运动内观察到的两个肺叶的BACE，以及界面区域。一个自我抑制的构象与侧链的Tyr71占据的S，口袋是存在于一些未绑定的模拟。由于Ser35羟基和胃蛋白酶样酶中保守的水分子的伴随重定向，催化Asp32和Ser35之间的侧链氢键的可逆损失提供了进一步的证据，表明Ser35有助于Asp32在催化过程中的质子接受和释放。
The aspartic protease beta-secretase (BACE) cleaves the amyloid precursor protein into a 42 residue beta-peptide, which is the principal biochemical marker of Alzheimer's disease. Multiple explicit-water molecular dynamics simulations of the apo and inhibitor bound structures of BACE indicate that both open- and closed-flap conformations are accessible at room temperature and should be taken into account for inhibitor design. Correlated motion is observed within each of the two lobes of BACE, as well as for the interfacial region. A self-inhibited conformation with the side chain of Tyr71 occupying the S, pocket is present in some of the unbound simulations. The reversible loss of the side chain hydrogen bond between the catalytic Asp32 and Ser35, due to the concomitant reorientation of the Ser35 hydroxyl group and a water molecule conserved in pepsin-like enzymes, provides further evidence for the suggestion that Ser35 assists in proton acceptance and release by Asp32 during catalysis.