Three-dimensional structures of Drosophila melanogaster acetylcholinesterase and of its complexes with two potent inhibitors
Three-dimensional structures of Drosophila melanogaster acetylcholinesterase and of its complexes with two potent inhibitors
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DOI：
10.1110/ps.9.6.1063
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发表时间：
2000-06-01
期刊：
影响因子：
8
通讯作者：
Sussman, JL
中科院分区：
文献类型：
--
作者：
Harel, M;Kryger, G;Sussman, JL
我们对果蝇乙酰胆碱酯酶进行了结晶，并在2.7埃分辨率下解析了果蝇乙酰胆碱酯酶及其与两种有效的可逆抑制剂1，2，3，4-tetrahydro-N-(phenylmethyl)-9-acridinamine和1，2，3，4-tetrahydro-N-(3-iodophenyl-methyl)-9-acridinamine-all-3的络合物的结构。黑腹毛虫乙酰胆碱酯酶的精细结构与脊椎动物(如人、小鼠和鱼)的乙酰胆碱酯酶相似，在整体折叠、电荷分布和深活性部位峡谷方面类似，但一些表面环偏离其在脊椎动物结构中的位置达8埃，C-末端螺旋发生显著移位。昆虫酶的活性部位峡谷明显比鱼雷的窄，并且其运动轨迹移动了几埃。昆虫酶峡谷下部的体积与脊椎动物酶的50%相似。当两个抑制剂中的任何一个结合时，活性部位峡谷内的九个芳香族侧链改变它们的构象，以便与抑制剂相互作用。昆虫和脊椎动物酶在活性和特异性上的一些差异可以通过比较它们的三维结构来解释。
We have crystallized Drosophila melanogaster acetylcholinesterase and solved the structure of the native enzyme and of its complexes with two potent reversible inhibitors, 1,2,3,4-tetrahydro-N-(phenylmethyl)-9-acridinamine and 1,2,3,4-tetrahydro-N-(3-iodophenyl-methyl)-9-acridinamine-all three at 2.7 Angstrom resolution. The refined structure of D. melanogaster acetylcholinesterase is similar to that of vertebrate acetylcholinesterases, for example, human, mouse, and fish, in its overall fold, charge distribution, and deep active-site gorge, but some of the surface loops deviate by up to 8 Angstrom from their position in the vertebrate structures, and the C-terminal helix is shifted substantially. The active-site gorge of the insect enzyme is significantly narrower than that of Torpedo californica AChE, and its trajectory is shifted several angstroms. The volume of the lower part of the gorge of the insect enzyme is similar to 50% of that of the vertebrate enzyme. Upon binding of either of the two inhibitors, nine aromatic side chains within the active-site gorge change their conformation so as to interact with the inhibitors. Some differences in activity and specificity between the insect and vertebrate enzymes can be explained by comparison of their three-dimensional structures.