C DAVID STOUT PRT TIME

C 大卫·斯托特 PRT 时间

• 批准号: 8169910
• 负责人: Charles David Stout
• 金额: $ 0.78万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8169910
• 关键词: Address; Binding; Carcinogens; Complex; Computer Retrieval of Information on Scientific Projects Database; Crystallization; Cytochrome P450; Engineering; Enzymes; Funding; Grant; Institution; Laboratory Study; Membrane; Membrane Proteins; Metabolic Activation; Methodology; Mono-S; Pathway interactions; Prostaglandins; Proteins; Reaction; Research; Research Personnel; Resolution; Resources; Source; Steroids; Sterols; Structural Models; Structure; Surface; Time; Toxic Environmental Substances; United States National Institutes of Health; chemical carcinogen; interest; protein structure; purge

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. (1) Eukaryotic cytochromes P450 (P450s) are ubiquitous, integral membrane enzymes that catalyze the mono-oxygenation of a large number of both exogenous and endogenous compounds. These reactions include pathways for the purging of environmental toxins and carcinogens, the synthesis of sterols, steroids and prostanoids and, in some cases, the metabolic activation of chemical carcinogens. A large number of laboratories study microsomal P450s and will benefit greatly from a structural model. We propose 1) to continue crystallographic studies of mammalian P450s to higher resolution in order to further characterize the membrane |attachment surface, 2) to determine what changes occur in the structure of the protein when substrate binds and the complex is reduced, and 3) to extend the crystallization methodology to related microsomal P450s of pharmacological interest. The structures to be determined in these studies will address questions about the interaction of the protein with the membrane as well as substrate binding and recognition. In addition, these studies will yield significant new information regarding modes of membrane binding, and may help to advance the methodology behind the engineering of membrane proteins for structural studies.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 (1) 真核细胞色素 P450 (P450s) 是普遍存在的完整膜酶，可催化大量外源和内源化合物的单氧化作用。这些反应包括清除环境毒素和致癌物的途径、甾醇、类固醇和前列腺素的合成，以及在某些情况下化学致癌物的代谢激活。许多实验室研究微粒体 P450，并将从结构模型中受益匪浅。我们建议 1) 继续对哺乳动物 P450 进行更高分辨率的晶体学研究，以进一步表征膜|附着表面，2) 确定当底物结合且复合物还原时蛋白质结构发生哪些变化，以及 3)将结晶方法扩展到具有药理学意义的相关微粒体 P450。这些研究中待确定的结构将解决有关蛋白质与膜相互作用以及底物结合和识别的问题。此外，这些研究将产生有关膜结合模式的重要新信息，并可能有助于推进用于结构研究的膜蛋白工程背后的方法。