INHIBITION OF ACETYLCHOLINESTERASE BY FASCICULIN MUTANTS
束蛋白突变体对乙酰胆碱酯酶的抑制
基本信息
- 批准号:8364303
- 负责人:
- 金额:$ 0.11万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-09-15 至 2013-07-31
- 项目状态:已结题
- 来源:
- 关键词:AcetylcholinesteraseAffinityAlzheimer&aposs DiseaseBindingBiochemistryBiomedical ResearchBiophysicsComplexDevelopmentDrug usageEnzymesFundingGrantHigh Performance ComputingHousingInduced MutationManuscriptsMolecularMuscle ContractionMutationNational Center for Research ResourcesPennsylvaniaPrincipal InvestigatorProteinsReportingResearchResearch InfrastructureResourcesRunningSignal TransductionSnake VenomsSourceStructureStudentsSupervisionSystemTimeUnited States National Institutes of HealthUniversitiesbasecostdesignfasciculingraduate studentmolecular dynamicsmutantnerve gasneurotransmissionsimulation
项目摘要
This subproject is one of many research subprojects utilizing the resources
provided by a Center grant funded by NIH/NCRR. Primary support for the subproject
and the subproject's principal investigator may have been provided by other sources,
including other NIH sources. The Total Cost listed for the subproject likely
represents the estimated amount of Center infrastructure utilized by the subproject,
not direct funding provided by the NCRR grant to the subproject or subproject staff.
The PI has been involved with molecular dynamics analyses of Acetylcholinesterase (AChE) since 1993, and other systems - some of which were performed at the PSC. This enzyme is critically involved in the transmission of nerve signals to muscle contraction, and it is the target of nerve gas agents as well as drugs used to treat Alzheimer(s disease. Fasciculin (Fas) is a component of snake venom that also targets AChE. A manuscript by Sussman et al, reviewed by the PI, and currently _in press_, reports that certain Fas mutants bind more avidly to AChE, but their affinity is not explained by examination of the static crystal structures. We have run CHARMm simulations of the AChE-Fas complex on a single-CPU SGI machine that suggest the discrepancies are a consequence of main chain distortions induced by the mutations. We are seeking PSC access to extend these CHARMm simulations and better explain why some mutations enhance, while others inhibit binding, contrary to predictions based on static analysis of the crystal structures. The conclusions will be relevant to many questions about protein design. The proposed studies will be performed by a graduate student in Biochemistry and Molecular Biophysics at the University of Pennsylvania, under the supervision of the PI. This student is already performing CHARMm simulations on in-house machines, so development time on PSC machines will be minimal. The project will continue until mid-September, or possibly December.
这个子项目是利用资源的许多研究子项目之一。
由NIH/NCRR资助的中心拨款提供。对子项目的主要支持
子项目的首席调查员可能是由其他来源提供的,
包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能
表示该子项目使用的中心基础设施的估计数量,
不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。
自1993年以来,PI一直参与乙酰胆碱酯酶(AChE)和其他系统的分子动力学分析-其中一些系统是在PSC进行的。这种酶在神经信号到肌肉收缩的传递中起着至关重要的作用,是神经毒气毒剂以及用于治疗阿尔茨海默病(S病)的药物的靶标。发酵素(Fas)是蛇毒的一种成分,也是AChE的靶标。Sussman等人的一篇手稿,由PI审阅,目前正在出版中,报告说某些Fas突变体更能与AChE结合,但它们的亲和力不能通过检查静态晶体结构来解释。我们在单CPU SGI机器上对AChE-Fas复合体进行了CHARMm模拟,表明这些差异是由突变引起的主链扭曲造成的。我们正在寻求PSC访问,以扩展这些CHARMm模拟,并更好地解释为什么一些突变增强,而另一些突变抑制结合,与基于晶体结构静态分析的预测相反。这些结论将与蛋白质设计的许多问题相关。拟议的研究将由宾夕法尼亚大学生物化学和分子生物物理学专业的一名研究生在PI的监督下进行。这个学生已经在内部机器上执行CHARMm模拟,因此在PSC机器上的开发时间将是最短的。该项目将持续到9月中旬,也可能是12月。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Paul H Axelsen其他文献
Paul H Axelsen的其他文献
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{{ truncateString('Paul H Axelsen', 18)}}的其他基金
INHIBITION OF ACETYLCHOLINESTERASE BY FASCICULIN MUTANTS
束蛋白突变体对乙酰胆碱酯酶的抑制
- 批准号:
8171919 - 财政年份:2010
- 资助金额:
$ 0.11万 - 项目类别:
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