Structural Evidence That Human Acetylcholinesterase Inhibited by Tabun Ages through O-Dealkylation
Structural Evidence That Human Acetylcholinesterase Inhibited by Tabun Ages through O-Dealkylation
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DOI：
10.1021/jm901853b
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发表时间：
2010-05-27
影响因子：
7.3
通讯作者：
Nachon, Florian
中科院分区：
文献类型：
--
作者：
Carletti, Eugenie;Colletier, Jacques-Philippe;Nachon, Florian
Tabun是一种通过催化丝氨酸的快速磷酸化来抑制人类乙酰胆碱酯酶（hAChE）的战剂。塔崩加合物上发生时间依赖性反应，导致“老化”酶，对肟再活化剂有抗性。老化反应可以通过脱烷基化或脱酰胺化进行，这取决于磷酰胺基加合物的立体化学。我们解决了X-射线结构肆虐塔崩hAChE与束状蛋白II复合，我们表明，通过O-脱烷基化的老化过程中，与我们确定的塔崩抑制人丁酰胆碱酯酶和小鼠乙酰胆碱酯酶的老化机制。值得注意的是，fasciculin II的老化和结合导致热稳定性的改善，这是由于在活性位点峡谷中彼此面对的两个亚结构域之间的额外稳定相互作用。这种被神经毒剂抑制的乙酰胆碱酯酶的第一种结构提供了对抑制和老化机制的结构洞察，以及用于设计能够重新激活老化乙酰胆碱酯酶的分子的结构模板。
Tabun is a warfare agent that inhibits human acetylcholinesterase (hAChE) by rapid phosphylation of the catalytic serine. A time-dependent reaction occurs on the tabun adduct, leading to an "aged" enzyme, resistant to oxime reactivators. The aging reaction may proceed via either dealkylation or deamidation, depending on the stereochemistry of the phosphoramidyl adduct. We solved the X-ray structure raged tabun hAChE complexed with fasciculin II, and we show that aging proceeds through O-dealkylation, in agreement with the aging mechanism that we determined for tabun-inhibited human butyrylcholinesterase and mouse acetylcholinesterase. Noteworthy, aging and binding of fasciculin II lead to an improved thermostability, resulting from additional stabilizing interactions between the two subdomains that face each other across the active site gorge. This first structure of hAChE inhibited by a nerve agent provides structural insight into the inhibition and aging mechanisms and a structural template for the design of molecules capable of reactivating aged hAChE.