Toxic Metal Complexation by de Novo Designed Peptides

de Novo 设计的肽与有毒金属络合

• 批准号: 7216676
• 负责人: VINCENT L PECORARO
• 金额: $ 26.99万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-09 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7216676
• 关键词: Achievement; Adverse effects; Affinity; Arsenic; Binding; Binding Sites; Biological; Biological Models; Biological Process; Brain Injuries; Cadmium; Cells; Cessation of life; Chloride Ion; Chlorides; Communities; Confusion; Copper; Coupled; Development; Drug Metabolic Detoxication; Elements; Encapsulated; Engineering; Environment; Evaluation; Excision; Exposure to; Foundations; Generations; Goals; Headache; Health; Heavy Metals; Human; Investigation; Ions; Kinetics; Knowledge; Lead; Lesion; Ligands; Location; Mercury; Metal Binding Site; Metalloproteins; Metals; Modeling; Modification; Nausea and Vomiting; Numbers; Object Attachment; Organism; Peptides; Placement; Process; Property; Proteins; Reactive Oxygen Species; Research; Research Personnel; Resolution; Series; Site; Skin; Solid; Solutions; Structure; Symptoms; System; Therapeutic; Thermodynamics; Toxic effect; Transition Elements; Treatment Protocols; Water; aqueous; base; design; exposed human population; genetic regulatory protein; improved; insight; metal poisoning; metalloregulatory protein; nervous system disorder; novel; peptide structure; polypeptide; prevent; programs; protein expression; resistance mechanism; respiratory; toxic metal

DESCRIPTION (provided by applicant): Heavy metal poisoning by elements such as mercury, lead, cadmium, and arsenic is a significant human health problem. Understanding the interaction of heavy metals with proteins is essential for defining the mechanism of toxicity, developing ways to minimize human exposure and to provide therapeutic regimens for removal of toxic ions. Our goals are (1) to develop peptide systems that provide a groundwork for the understanding of metalloregulatory proteins and metallochaperones, (2) to develop peptidic systems that can efficiently and selectively sequester heavy metal ions from aqueous solutions, and (3) to understand the thermodynamics and kinetics of metal binding to these designed peptides. To achieve these goals we will use a de novo peptide system based on the three-stranded coiled coil peptide aggregate motif that encapsulates with high affinity single heavy metal ions and provides spectroscopic models of mercury, cadmium and arsenic binding sites in biological systems. We will generate high resolution structures of this peptide system in the presence and absence of these heavy metals, elucidate the kinetic and thermodynamic mechanisms of heavy metal encapsulation, and expand the array of characterized systems to transition metal ions Fe(II), Cu(I), Ni(II), Co(II) and Zn(II). We will also extend the original design to include single chain peptides that encapsulate heavy metals and coiled coils that provide different coordination environments than the original design and those that encapsulate more than one heavy metal ion. These studies will expand the foundation of knowledge that has been laid by the scientific community investigating metallopeptide design, metalloregulatory proteins and heavy metal detoxification. These objectives will develop insight into the interplay between metal coordination and apopeptide structure in defining the overall metallopeptide fold, an important aspect of metallopeptide design. Also, development of highly efficient and specific heavy metal sequestering peptides could, ultimately, provide a viable and biodegradable means of removing heavy metals from contaminated water.

描述（由申请人提供）：由汞，铅，镉和砷等元素进行的重金属中毒是一个重大的人类健康问题。了解重金属与蛋白质的相互作用对于定义毒性机制，开发方法以最大程度地限制人类暴露并提供治疗方案以去除有毒离子是必不可少的。 我们的目标是（1）开发肽系统，为理解金属调节蛋白和金属色蛋白提供基础，（2）开发可以有效，有选择性地选择性地从水溶液中隔离重金属离子的肽系统，（3）以了解与这些设计的peptidese的热力学和动力学结合的热力学和动力学。 为了实现这些目标，我们将使用基于三链盘绕的盘绕肽聚集体的新肽系统，该基序概括了高亲和力单重金属离子，并提供了生物系统中汞，镉和砷结合位点的光谱模型。在存在和不存在这些重金属的情况下，我们将生成该肽系统的高分辨率结构，阐明重金属封装的动力学和热力学机制，并将一系列特征化的系统扩展到过渡金属离子Fe（II），Cu（ii），Cu（i），Ni（i），Ni（ii），CO（II），CO（II）和Zn（II）。我们还将将原始设计扩展到包含封装重金属和盘绕线圈的单链肽，这些肽提供了与原始设计不同的配位环境以及封装多个重金属离子的固定环境。 这些研究将扩大科学界研究金属肽设计，金属调节蛋白和重金属排毒的知识的基础。这些目标将在定义总体金属肽折叠时洞悉金属配位和叠肽结构之间的相互作用，这是金属肽设计的重要方面。同样，高效和特定的重金属隔离肽的发展最终可能会提供一种可行且可生物降解的方法，用于从受污染的水中去除重金属。