Overlay independent X-ray data analysis for enhanced oxime OP-ChE reactivation

叠加独立 X 射线数据分析，增强肟 OP-ChE 重新激活

• 批准号: 9209336
• 负责人: Zoran Radic
• 金额: $ 15.5万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9209336
• 关键词: Acetylcholinesterase; Algorithms; Amino Acids; Antidotes; Architecture; Binding; Breathing; Butyrylcholinesterase; Carbon; Catalysis; Cholinesterases; Computer software; Data; Data Analyses; Data Collection; Databases; Deposition; Development; Electronics; Goals; Human; Individual; Intoxication; Ligands; Liquid substance; Manuals; Measures; Military Personnel; Movement; Nature; Organophosphates; Output; Oximes; Pesticides; Phosphorus; Physiological; Poisoning; Population; Predisposition; Procedures; Protein Conformation; Proteins; Reaction; Research Personnel; Resolution; Roentgen Rays; Side; Sodium Chloride; Solid; Structure; Syria; Temperature; Tertiary Protein Structure; Testing; Vertebral column; analytical tool; base; cold temperature; computerized tools; design; expectation; flexibility; graphical user interface; hazard; nerve agent; novel strategies; pesticide exposure; protein structure; solid state; tool; toxic organophosphate insecticide exposure; user-friendly

Overlay independent X-ray data analysis for enhanced oxime OP-ChE reactivation Project Summary. Vulnerability of large civilian and military populations to organophosphate (OP) exposure remains an unfortunate peril of the present day. Both, nerve agent OPs and OP based pesticides are realistic and alarmingly significant hazards. Recent horrifying massive nerve agent poisoning episodes in Syria and daily worldwide fatalities associated with OP based pesticide exposures reveal general lack of appropriateness of currently employed measures for counteracting OP intoxications. The emphasis is on affordability, availability and efficacy. More than two hundred AChE and BChE structures deposited in PDB in the past 25 years reveal unusually consistent protein conformations, not only of protein backbones but also of majority of amino acid side chains. This apparent absence of conformational flexibility registered at the low temperature and in the solid crystaline state, appears as a contrast to an extreemely high catalytic output, in particular in the long and narrow AChE active center gorge. Catalytically essential, thermally driven, „breathing“ fluctuations of the AChE and BChE protein backbones have long been suspected and proposed but have never been clearly demonstrated experimentally. In particular for oxime reactivation reactions backbone fluctuations appear essential due to highly restricted access to covalently attached OPs in the narrow actice center space impacted further by covalently bound OP conjugates. For design of an accelerated, efficient reactivator molecule it is critical to know what parts of active center have structural predisposition to move and facilitate nucleophilic oxime approach to the phosphorus atom in geometrically optimal fashion. This information is encripted in hundreds of resolved and deposited ChE structures and our goal is to extract it to an useful form. We expect to detect structural fluctuations small in magnitude yet systematic in nature. Our initial manual analyses confirm those expectations.

覆盖独立的X射线数据分析，用于增强的氧气卫生复活 项目摘要。大型平民和军事人口的脆弱性 有机磷酸盐（OP）暴露仍然是当今不幸的危险。两者，神经剂OPS 基于OP的农药是现实且令人震惊的危险。最近恐怖的大神经 叙利亚的特工中毒发作和与基于OP的农药有关的每日全球死亡人数 暴露揭示了当前采用措施来抵消OP的普遍缺乏适当性 intexations。重点是可用性，可用性和效率。超过200多个疼痛和 在过去25年中沉积在PDB中的BCHE结构表现出异常一致的蛋白质构象， 不仅是蛋白质骨架，而且是大多数氨基酸侧链。这种显然没有 在低温和固体结晶状态下注册的构象柔韧性似乎是 与极高的催化输出形成鲜明对比，尤其是在长而狭窄的ACHE活动中心 峡谷。催化性必不可少的，热驱动的，“呼吸” ACHE和BCHE蛋白的波动 长期以来一直怀疑和提出过骨架，但从未清楚地证明 实验。尤其是氧反应反应反应主链波动似乎是必不可少的 在狭窄的影响中心空间中，高度限制访问共价附加的OPS，进一步影响 共价约束OP共轭。为了设计加速，有效的重新激活分子，至关重要 知道活性中心的哪些部分具有移动和促进核直线智质的结构易感性 以几何最佳方式对磷原子的方法。此信息被打入 数百个已解决和沉积的CHE结构，我们的目标是将其提取为有用的形式。 我们期望检测到幅度较小但本质上有系统的结构波动。我们的最初 手动分析证实了这些期望。