Confining Metal Complexes within Protein Hosts: Models for Metalloprotein Active Sites

将金属配合物限制在蛋白质宿主内：金属蛋白质活性位点模型

• 批准号: 10365553
• 负责人: Andrew S. Borovik
• 金额: $ 30.11万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10365553
• 关键词: Active Sites; Affect; Aging; Binding; Biomimetics; Biotin; Chemicals; Comparative Study; Complex; Detection; Development; Dioxygen; Engineering; Ensure; Environment; Excision; Functional disorder; Glare; Goals; Health; Human; Hydrogen Bonding; Immobilization; Link; Location; Magnetism; Metalloproteins; Metals; Methane hydroxylase; Methods; Mixed Function Oxygenases; Modeling; Molecular; Molecular Biology; Mononuclear; Mutation; Operating System; Oxidation-Reduction; Oxides; Oxygenases; Positioning Attribute; Process; Property; Proteins; Regulation; Reproducibility; Research; Ribonucleotide Reductase; Science; Side; Site; Streptavidin; Structure; Structure-Activity Relationship; Synthesis Chemistry; System; Technology; Tyrosine; Water; aqueous; chemical property; cofactor; design; improved; metal complex; physical property; programs; protein function; protein structure function; small molecule; structural biology; tool

This research will develop methods to model active sites in metalloproteins for the purpose of determining fundamental structure-function relationships for how proteins activate dioxygen, a process that strongly impacts human health and aging. Artificial metallproteins will be prepared utilizing biotin-streptavidin technology as a tool to ensure specific and reproducible placement of synthetic metal complexes within protein hosts. This approach is proposed to be an effective method to model key properties of the active sites in native metalloproteins, including site isolation of species, regulation of the primary coordination sphere, and control of the microenvironments around the metal complexes. One glaring weakness of many biomimetic systems is their limited ability to regulate the microenvironments that surround metal centers. No chemical system operates in isolation without interacting with its local environment. There is a growing body of evidence from structural biology that the microenvironment, a space around metal complexes that comprises the secondary coordination sphere, has profound effects on protein function that ranges from modulation of physical properties to delivery of reactants and removal of products. It is our contention that the greater regulation of microenvironments will lead to better understanding of protein function. It is further maintained that the benefits gained from fundamental analyses as proposed in this application extend well beyond improvements in selectivities/efficiencies at the molecular level – they are transformative for all types of platforms, providing the requisite information that is still missing for the development of highly functional systems. We propose an approach for preparing artificial metalloproteins that allows for the confinement of synthetic complexes within protein hosts to regulate both the primary and secondary coordination spheres about the immobilized metal centers. The ability to regulate these coordination spheres within a protein will produce systematic structure-function relationships that will lead to an improved understanding of chemical processes that are directly linked to human health.

这项研究将开发方法，以建模金属蛋白中的活性位点是为了 确定蛋白质如何激活二恶英的基本结构 - 函数 强烈影响人类衰老的过程。 利用生物素 - 链霉亲素技术作为确保特定和可重现的放置 蛋白质宿主中的合成金属络合物是一种有效的 建模活性属性的方法坐落在本机金属蛋白中，包含位点 物种的隔离，主要协调球的调节以及控制 金属复合物周围的微环境。 系统是他们调节金属中心围绕的微环境的有限能力。 没有化​​学系统在没有与局部环境相互作用的情况下孤立地运行。 从结构生物学的越来越多的证据，即微环境，周围的空间 包括次级配位球的金属配合物对 蛋白质功能范围从物理特性的调节到反应物的递送和 去除产品。 我们的论点是，更大的微环境调节将导致更好 了解蛋白质功能。 该应用程序中所提供的基本分析远远超出了改进的范围 分子水平的选择性/效率 - 它们对于所有类型 平台，提供必要的信息开发的发展 高功能系统。 我们提出了一种预制金属蛋白的方法 蛋白质宿主内的合成复合物的调节 围绕着金属中心的协调能力。 蛋白质内的协调球将产生系统的结构功能关系 这将导致对化学过程直接相关的化学过程的理解 人类健康。