Structural insights into ligand interactions at the acetylcholinesterase peripheral anionic site
Structural insights into ligand interactions at the acetylcholinesterase peripheral anionic site
复制标题
DOI：
10.1093/emboj/cdg005
复制
发表时间：
2003-01-02
期刊：
影响因子：
11.4
通讯作者：
Marchot, P
中科院分区：
文献类型：
--
作者：
Bourne, Y;Taylor, P;Marchot, P
乙酰胆碱酯酶(AChE)的外周阴离子位点位于活性中心峡谷入口处，包含变构激活剂和抑制剂的重叠结合位点；然而，该位点与峡谷基地的活性中心偶联以调节催化的分子机制尚不清楚。外周部位也被认为与突触发生或神经退行性变过程中发生的异源蛋白联系有关。一种新颖的小鼠AChE晶体形式，结合晶体的分光光度分析，使我们能够解决AChE的独特结构：具有自由外围中心的AChE，以及具有外围中心抑制剂的三种络合物：苯基菲并菲配体，分贝和丙酸，以及焦性没食子酸配体，加拉胺，分辨率为2.20-2.35埃。与AChE与肽束蛋白或有机双功能抑制剂的复合体的结构进行比较，揭示了有助于外围位点配体相互作用的新的结构决定因素，并允许详细描绘该位点的地形。因此，这些结构为设计针对酶表面的化合物提供了模板，这些化合物调节控制催化活性和非催化异源蛋白质结合的特定表面相互作用。
The peripheral anionic site on acetylcholinesterase (AChE), located at the active center gorge entry, encompasses overlapping binding sites for allosteric activators and inhibitors; yet, the molecular mechanisms coupling this site to the active center at the gorge base to modulate catalysis remain unclear. The peripheral site has also been proposed to be involved in heterologous protein associations occurring during synaptogenesis or upon neurodegeneration. A novel crystal form of mouse AChE, combined with spectrophotometric analyses of the crystals, enabled us to solve unique structures of AChE with a free peripheral site, and as three complexes with peripheral site inhibitors: the phenylphenanthridinium ligands, decidium and propidium, and the pyrogallol ligand, gallamine, at 2.20-2.35 Angstrom resolution. Comparison with structures of AChE complexes with the peptide fasciculin or with organic bifunctional inhibitors unveils new structural determinants contributing to ligand interactions at the peripheral site, and permits a detailed topographic delineation of this site. Hence, these structures provide templates for designing compounds directed to the enzyme surface that modulate specific surface interactions controlling catalytic activity and non-catalytic heterologous protein associations.