Overlay independent X-ray data analysis for enhanced oxime OP-ChE reactivation
Overlay independent X-ray data analysis for enhanced oxime OP-ChE reactivation
批准号:
9356345
负责人:
Zoran Radic
金额:
$15.5万
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-09-30 至 2019-08-31
关键词:
AcetylcholinesteraseAlgorithmsAmino AcidsAntidotesArchitectureBreathingButyrylcholinesteraseCarbonCatalysisCholinesterasesComputer softwareDataData AnalysesData CollectionDatabasesDepositionDevelopmentGoalsHumanIndividualIntoxicationIntuitionLigandsLiquid substanceManualsMathematicsMeasuresMilitary PersonnelMolecular ConformationMovementNatureOrganophosphatesOutputOximesPesticidesPhosphorusPhysiologicalPoisoningPopulationPredispositionProceduresProtein ConformationProteinsReactionResearch PersonnelResolutionRoentgen RaysSideSodium ChlorideSolidStructureSyriaTemperatureTertiary Protein StructureTestingVertebral columnanalytical toolbasecold temperaturecomparativecomputerized toolsdesignexpectationflexibilitygraphical user interfacehazardnerve agentnovel strategiespesticide exposureprotein structuresolid statetooltoxic organophosphate insecticide exposureuser-friendly
中文摘要
叠加独立 X 射线数据分析,增强肟 OP-ChE 重新激活
项目摘要。大量平民和军人容易受到
有机磷(OP)暴露至今仍然是一个不幸的危险。两者,神经毒剂OP
有机磷农药是现实且令人震惊的重大危害。最近恐怖的巨大神经
叙利亚发生的药剂中毒事件以及全球每天与有机磷农药相关的死亡事件
暴露揭示了目前采用的应对OP措施普遍缺乏适当性
中毒。重点是可负担性、可用性和功效。超过 200 个 AChE 和
过去 25 年沉积在 PDB 中的 BChE 结构揭示了异常一致的蛋白质构象,
不仅是蛋白质主链,而且是大多数氨基酸侧链。这种明显的缺失
在低温和固态晶体状态下记录的构象灵活性,表现为
与极高的催化输出形成对比,特别是在又长又窄的 AChE 活性中心
峡谷。 AChE 和 BChE 蛋白的催化必需、热驱动、“呼吸”波动
骨干网长期以来一直被怀疑和提出,但从未得到明确证明
实验性地。特别是对于肟再活化反应,主链波动似乎至关重要,因为
在狭窄的活动中心空间中,对共价连接的OP的访问受到高度限制,进一步受到影响
共价结合的 OP 缀合物。对于加速、高效的再激活分子的设计来说,至关重要的是
了解活性中心的哪些部分具有移动和促进亲核肟的结构倾向
以几何最佳方式接近磷原子。该信息被记录在
数百个已解析和沉积的 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虽小但本质上是系统性的结构波动。我们最初的
手动分析证实了这些预期。
英文摘要
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.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
In Vivo Efficacy of Novel Uncharged Bis-Oximes in OP Poisoning Treatment
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批准号:10412696
-
项目类别:
-
资助金额:$20.98万
-
财政年份:2022
-
负责人:Zoran Radic
-
依托单位:
Refined uncharged Bis-Oximes for Rapid CNS Reactivation of OP-Inhibited hAChE.
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批准号:10582723
-
项目类别:
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资助金额:$19.27万
-
财政年份:2022
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负责人:Zoran Radic
-
依托单位:
Refined uncharged Bis-Oximes for Rapid CNS Reactivation of OP-Inhibited hAChE.
-
批准号:10407766
-
项目类别:
-
资助金额:$24.69万
-
财政年份:2022
-
负责人:Zoran Radic
-
依托单位:
In Vivo Efficacy of Novel Uncharged Bis-Oximes in OP Poisoning Treatment
-
批准号:10598635
-
项目类别:
-
资助金额:$15.58万
-
财政年份:2022
-
负责人:Zoran Radic
-
依托单位:
Overlay independent X-ray data analysis for enhanced oxime OP-ChE reactivation
-
批准号:9209336
-
项目类别:
-
资助金额:$15.5万
-
财政年份:2016
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负责人:Zoran Radic
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依托单位:
Accelerated AChE Reactivator Design by Mechanistic Neutron Scattering Studies
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批准号:8735548
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项目类别:
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资助金额:$70.95万
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财政年份:2014
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负责人:Zoran Radic
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依托单位:
Accelerated AChE Reactivator Design by Mechanistic Neutron Scattering Studies
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批准号:8892277
-
项目类别:
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资助金额:$67.02万
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财政年份:2014
-
负责人:Zoran Radic
-
依托单位:
Accelerated AChE Reactivator Design by Mechanistic Neutron Scattering Studies
-
批准号:9632884
-
项目类别:
-
资助金额:$3.16万
-
财政年份:2014
-
负责人:Zoran Radic
-
依托单位:
BChE reactivators for nerve agent and pesticide OP detoxification in human tissue
-
批准号:8610134
-
项目类别:
-
资助金额:$41.27万
-
财政年份:2013
-
负责人:Zoran Radic
-
依托单位:
BChE reactivators for nerve agent and pesticide OP detoxification in human tissue
-
批准号:8738731
-
项目类别:
-
资助金额:$38.52万
-
财政年份:2013
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负责人:Zoran Radic
-
依托单位:
Optimization of nonpyridinium oximes for BChE hydrolysis of OPs in plasma
-
批准号:8020885
-
项目类别:
-
资助金额:$41.58万
-
财政年份:2010
-
负责人:Zoran Radic
-
依托单位:
Optimization of nonpyridinium oximes for BChE hydrolysis of OPs in plasma
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批准号:8153134
-
项目类别:
-
资助金额:$41.38万
-
财政年份:2010
-
负责人:Zoran Radic
-
依托单位:
Optimization of nonpyridinium oximes for BChE hydrolysis of OPs in plasma
-
批准号:8508593
-
项目类别:
-
资助金额:$7.75万
-
财政年份:2010
-
负责人:Zoran Radic
-
依托单位:
海外基金