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
• 负责人: Paul H Axelsen
• 金额: $ 0.11万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8171919
• 关键词: Acetylcholinesterase; Affinity; Alzheimer' s Disease; Binding; Biochemistry; Biophysics; Complex; Computer Retrieval of Information on Scientific Projects Database; Development; Drug usage; Enzymes; Funding; Grant; Housing; Induced Mutation; Institution; Manuscripts; Molecular; Muscle Contraction; Mutation; Pennsylvania; Proteins; Reporting; Research; Research Personnel; Resources; Running; Signal Transduction; Snake Venoms; Source; Structure; Students; Supervision; System; Time; United States National Institutes of Health; Universities; base; design; fasciculin; graduate student; molecular dynamics; mutant; nerve gas; neurotransmission; simulation

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 自1993年以来，PI一直参与乙酰胆碱酯酶（ACHE）的分子动力学分析，而其他系统则是在PSC上进行的。 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，但它们的亲和力不是通过对静态晶体结构的检查来解释的。结构。结论将与宾夕法尼亚大学的生物化学和分子生物物理学的研究生在PI的监督下进行许多有关蛋白质设计的问题。该学生已经在内部机器上进行了CHARMM模拟，因此PSC机器上的开发时间将很小。该项目将持续到9月中旬或可能是12月。