Crystallographic Snapshots of Nonaged and Aged Conjugates of Soman with Acetylcholinesterase, and of a Ternary Complex of the Aged Conjugate with Pralidoxime
Crystallographic Snapshots of Nonaged and Aged Conjugates of Soman with Acetylcholinesterase, and of a Ternary Complex of the Aged Conjugate with Pralidoxime
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DOI：
10.1021/jm900433t
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发表时间：
2009-12-10
影响因子：
7.3
通讯作者：
Weik, Martin
中科院分区：
文献类型：
--
作者：
Sanson, Benoit;Nachon, Florian;Weik, Martin
有机磷化合物（OP）是乙酰胆碱酯酶（AChE）的强抑制剂，可引起人体中毒. OP梭曼对乙酰胆碱酯酶的抑制涉及催化丝氨酸的磷酸化，随后的脱烷基化产生一种称为“老化”酶的形式。未老化的形式可以在一定程度上被亲核试剂，如解磷定（2-PAM）重新激活，而OP抑制的AChE的老化形式完全抵抗重新激活。本文研究了梭曼对乙酰胆碱酯酶（TcAChE）前体结构的影响。未老化共轭物中梭曼立体异构体加合物的绝对构型为PSCR。在老化过程中观察到催化His 440侧链的结构重新取向。此外，老化共轭物与2-PAM的三元复合物的晶体结构显示，肟功能的取向不允许亲核攻击油的磷原子，从而提供了一个合理的解释，其未能重新激活老化梭曼/乙酰胆碱酯酶共轭物。总之，这三种晶体结构为设计新的再活化剂提供了实验基础。
Organophosphate compounds (OP) ire potent inhibitors of acetylcholinesterases (AChEs) and can cause lethal poisoning in humans. Inhibition of AChEs by the OP soman involves phosphonylation of the catalytic serine, and subsequent dealkylation produces a form known as the "aged" enzyme. The nonaged form can be reactivated to a certain extent by nucleophiles, such as pralidoxime (2-PAM), whereas aged forms of OP-inhibited AChEs are totally resistant to reactivation. Here, we solved the X-ray crystal Structures of AChE front Torpedo californica (TcAChE) conjugated with soman before and after aging. The absolute configuration of the soman stereoisomer adduct in the nonaged conjugate is PSCR. A Structural reorientation of the catalytic His440 side chain was observed during the aging process. Furthermore, the crystal structure of the ternary complex of the aged conjugate with 2-PAM revealed that the orientation of the oxime function does not permit nucleophilic attack oil the phosphorus atom, thus providing a plausible explanation for its failure to reactivate the aged soman/AChE conjugate. Together, these three Crystal Structures provide an experimental basis for the design of new reactivators.