Toxic Metal Complexation by de Novo Designed Peptides

de Novo 设计的肽与有毒金属络合

• 批准号: 8230719
• 负责人: VINCENT L PECORARO
• 金额: $ 26.74万
• 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 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8230719
• 关键词: Acute; Address; Adverse effects; Affinity; Amino Acids; Arsenic; Bacteria; Binding; Binding Sites; Biochemistry; Biological; Biological Process; Blood; Brain Injuries; Cadmium; Cessation of life; Chemistry; Child; Chronic; Communities; Complex; Confusion; Copper; Crystallography; Cysteine; DNA; DNA-Protein Interaction; Drug Metabolic Detoxication; Elements; Encapsulated; Environment; Evaluation; Excision; Exposure to; Foundations; Generations; Genetic Transcription; Goals; Headache; Health; Heavy Metals; Histidine; Human; Individual; Ions; Kinetics; Knowledge; Lead; Ligands; Location; Long-Term Effects; Mercury; Metal Binding Site; Metalloproteins; Metals; Modeling; Molecular; Molecular Chaperones; NMR Spectroscopy; Nausea and Vomiting; Organism; Peptides; Process; Property; Protein Binding; Proteins; Reaction; Reactive Oxygen Species; Regimen; Reporting; Repressor Proteins; Research; Resolution; Series; Site; Solutions; Specificity; Structure; Sulfhydryl Compounds; Symptoms; System; Therapeutic; Thermodynamics; Time; Toxic effect; Toxin; Transition Elements; Water; Work; Zinc; abstracting; aqueous; base; biological systems; design; exposed human population; fungus; insight; interest; metal poisoning; metalloregulatory protein; molecular recognition; novel; peptide structure; polypeptide; preference; prevent; resistance mechanism; respiratory; small molecule; success; toxic metal

DESCRIPTION (provided by applicant): Abstract 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 the removal of toxic ions. Our goals are (1) to develop peptide systems that provide a foundation for understanding metal binding by metalloregulatory proteins and metallochaperones, (2) to understand the thermodynamics and kinetics of heavy metals in helical assemblies and (3) to prepare new designed peptides utilizing different ligands (e.g., histidine or D-amino acids) or asymmetric binding sites in single polypeptides that fold into 1-helical bundles. 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 include single chain peptides that encapsulate heavy metals, 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. PUBLIC HEALTH RELEVANCE: Relevance to Human Health Heavy metals such as PbII, HgII, AsII and CdII cause severe health concerns due both to their acute toxicity and the long term effects of chronic exposure (e.g., the EPA estimated in 2002 that over 300,000 children in the USA had blood levels exceeding 10 ?g/dL). Our studies address these concerns in numerous ways: including making mimics of heavy metal binding sites in proteins in order to understand how heavy metals bind to proteins, defining the rates at which reactions occur and establishing the thermodynamic preferences of these metals to different sites. We are also relating this work to studies on proteins used to recognize or detoxify heavy metals in bacteria, fungi and humans (e.g., assessing how HgII interacts with the human copper chaperone HAH1).

描述（由申请人提供）： 汞、铅、镉、砷等重金属元素的中毒是一个严重的人类健康问题。了解重金属与蛋白质的相互作用对于确定毒性机制，开发最大限度地减少人类暴露的方法以及提供去除有毒离子的治疗方案至关重要。我们的目标是（1）开发肽系统，为理解金属调节蛋白和金属伴侣的金属结合提供基础，（2）理解螺旋组装体中重金属的热力学和动力学，以及（3）利用不同的配体（例如，组氨酸或D-氨基酸）或折叠成1-螺旋束的单个多肽中的不对称结合位点。为了实现这些目标，我们将使用一个从头肽系统的基础上的三链卷曲螺旋肽聚集体基序，封装高亲和力的单一重金属离子，并提供光谱模型的汞，镉，砷结合位点的生物系统。我们将产生高分辨率的结构，在这些重金属的存在和不存在下，这个肽系统，阐明重金属封装的动力学和热力学机制，并扩大阵列的特征系统，包括单链肽封装重金属，卷曲的线圈，提供不同的协调环境比原来的设计和那些封装一个以上的重金属离子。这些研究将扩大科学界调查金属肽设计、金属调节蛋白和重金属解毒所奠定的知识基础。这些目标将深入了解金属配位和载脂蛋白肽结构之间的相互作用，在定义的整体金属肽折叠，金属肽设计的一个重要方面。公共卫生相关性：重金属如PbII、HgII、AsII和CdII由于其急性毒性和慢性暴露的长期影响（例如，美国环保署在2002年估计，在美国有超过30万儿童的血液浓度超过10？g/dL）。我们的研究以多种方式解决了这些问题：包括模拟蛋白质中的重金属结合位点，以了解重金属如何与蛋白质结合，定义反应发生的速率，并建立这些金属对不同位点的热力学偏好。我们还将这项工作与用于识别或解毒细菌，真菌和人类中重金属的蛋白质的研究（例如，评估HgII如何与人铜分子伴侣HAH 1相互作用）。