Structure of a prereaction complex between the nerve agent sarin, its biological target acetylcholinesterase, and the antidote HI-6

Allgardsson Anders; Berg Lotta; Akfur ChristineHornberg AndreasWorek FranzLinusson AnnaEkstrom Fredrik J.

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Structure of a prereaction complex between the nerve agent sarin, its biological target acetylcholinesterase, and the antidote HI-6

机译：Structure of a prereaction complex between the nerve agent sarin, its biological target acetylcholinesterase, and the antidote HI-6

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Organophosphorus nerve agents interfere with cholinergic signaling by covalently binding to the active site of the enzyme acetylcholinesterase (AChE). This inhibition causes an accumulation of the neurotransmitter acetylcholine, potentially leading to overstimulation of the nervous system and death. Current treatments include the use of antidotes that promote the release of functional AChE by an unknown reactivation mechanism. We have used diffusion trap cryocrystallography and density functional theory (DFT) calculations to determine and analyze prereaction conformers of the nerve agent antidote HI-6 in complex with Mus musculus AChE covalently inhibited by the nerve agent sarin. These analyses reveal previously unknown conformations of the system and suggest that the cleavage of the covalent enzyme-sarin bond is preceded by a conformational change in the sarin adduct itself. Together with data from the reactivation kinetics, this alternate conformation suggests a key interaction between Glu202 and the O-isopropyl moiety of sarin. Moreover, solvent kinetic isotope effect experiments using deuterium oxide reveal that the reactivation mechanism features an isotope-sensitive step. These findings provide insights into the reactivation mechanism and provide a starting point for the development of improved antidotes. The work also illustrates how DFT calculations can guide the interpretation, analysis, and validation of crystallographic data for challenging reactive systems with complex conformational dynamics.

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《Proceedings of the National Academy of Sciences of the United States of America》 |2016年第20期|5514-5519|共6页
作者
Allgardsson Anders; Berg Lotta; Akfur ChristineHornberg AndreasWorek FranzLinusson AnnaEkstrom Fredrik J.;
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作者单位

Umea Univ, Dept Chem, SE-90187 Umea, Sweden;

Swedish Def Res Agcy, Dept CBRN Def & Secur, SE-90182 Umea, Sweden;

SP Processum AB, SE-89122 Ornskoldsvik, SwedenBundeswehr Inst Pharmacol & Toxicol, Dept Toxicol Enzymol, D-80937 Munich, Germany;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
acetylcholinesterase; density functional theory; crystallography; nerve agent; reactivation;

Structure of a prereaction complex between the nerve agent sarin, its biological target acetylcholinesterase, and the antidote HI-6

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