Crystal structures of acetylcholinesterase in complex with HI-6, Ortho-7 and obidoxime:: Structural basis for differences in the ability to reactivate tabun conjugates
Crystal structures of acetylcholinesterase in complex with HI-6, Ortho-7 and obidoxime:: Structural basis for differences in the ability to reactivate tabun conjugates
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DOI：
10.1016/j.bcp.2006.05.027
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发表时间：
2006-08-28
影响因子：
5.8
通讯作者：
Borjegren, Susanne
中科院分区：
文献类型：
--
作者：
Ekstrom, Fredrik;Pang, Yuan-Ping;Borjegren, Susanne
农药和神经毒剂等有机磷化合物对乙酰胆碱酯酶（ACNE）的抑制可导致中毒者急性中毒或死亡。某些肟类化合物可使抑制的ACNE重新激活，作为临床治疗OP中毒的解毒剂。肟HI-6、邻7和双肟与小鼠乙酰胆碱酯酶（mAChE）复合物的晶体结构揭示了外周阴离子位点（PAS）在肟结合中的不同作用。Trp 286和Asp 74侧链的有限结构变化促进了HI-6的4-羧酰胺吡啶鎓环插入Tyr 124和Trp 286侧链之间。HI-6的2-羧基亚氨基吡啶鎓环容纳在催化位点的入口处，肟酸盐与Phe 295的主链氮原子形成氢键。与HI-6相反，PAS内邻位-7和双肟的配位通过Trp 286的扩展结构变化而促进，该结构变化允许羧基亚氨基吡啶环之一与Tyr 72和Trp 286的芳族基团形成阳离子-π相互作用。邻位-7和双肟的中心链在活性位点峡谷中松散地配位，而第二个羧基亚氨基吡啶环被容纳在Tyr 337的苯酚环附近。结构数据清楚地表明类似的协调邻-7和双肟内的活性位点峡谷的痤疮。在终点再活化实验中，HI-6、Ortho-7和双肟的再活化效率分别为1%、45%和38%。HI-6的低效率和Ortho-7和双肟的显著更高的效率可以通过PAS和ACNE的活性位点峡谷中肟的差异结合来解释。(c)2006年爱思唯尔公司All rights reserved.
Inhibition of acetylcholinesterase (ACNE) by organophosphorus compounds (OPs) such as pesticides and nerve agents causes acute toxicity or death of the intoxicated individual. The inhibited ACNE may be reactivated by certain oximes as antidotes for clinical treatment of OP-intoxications. Crystal structures of the oximes HI-6, Ortho-7 and obidoxime in complex with Mus musculus acetylcholinesterase (mAChE) reveal different roles of the peripheral anionic site (PAS) in the binding of the oximes. A limited structural change of the side chains of Trp286 and Asp74 facilitates the intercalation of the 4-carboxylamide pyridinium ring of HI-6 between the side chains of Tyr124 and Trp286. The 2-carboxyimino pyridinium ring of HI-6 is accommodated at the entrance of the catalytic site with the oximate forming a hydrogen bond to the main-chain nitrogen atom of Phe295. In contrast to HI-6, the coordination of Ortho-7 and obidoxime within the PAS is facilitated by an extended structural change of Trp286 that allows one of the carboxyimino pyridinium rings to form a cation-pi interaction with the aromatic groups of Tyr72 and Trp286. The central chain of Ortho-7 and obidoxime is loosely coordinated in the active-site gorge, whereas the second carboxyimino pyridinium ring is accommodated in the vicinity of the phenol ring of Tyr337. The structural data clearly show analogous coordination of Ortho-7 and obidoxime within the active-site gorge of ACNE. Different ability to reactivate ACNE inhibited by tabun is shown in end-point reactivation experiments where HI-6, Ortho-7 and obidoxime showed an efficiency of 1, 45 and 38%, respectively. The low efficiency of HI-6 and the significantly higher efficiency of Ortho-7 and obidoxime may be explained by the differential binding of the oximes in the PAS and active-site gorge of ACNE. (c) 2006 Elsevier Inc. All rights reserved.