Molecular Mechanisms of the Evolution of Steroid Receptor-Ligand Interactions

类固醇受体-配体相互作用进化的分子机制

• 批准号: 8212332
• 负责人: Michael Jonathan Harms
• 金额: $ 5.39万
• 依托单位: UNIVERSITY OF OREGON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8212332
• 关键词: Affinity; Aldosterone; Amino Acid Sequence; Amino Acids; Asthma; Binding; Biophysics; Chemicals; Complex; Disease; Estrogen Receptors; Evolution; Family; Gene Duplication; Gene Family; Genetic Epistasis; Genetic Transcription; Goals; Growth; Hormones; Human; Hydrocortisone; Individual; Investigation; Ligands; Malignant Neoplasms; Measurement; Mediating; Methods; Molecular; Molecular Biology; Mutation; Pathway interactions; Pharmaceutical Preparations; Phylogenetic Analysis; Play; Protein Family; Proteins; Receptor Gene; Recording of previous events; Regulation; Relative (related person); Role; Signal Transduction; Specificity; Steroid Receptors; System; Techniques; Testing; Therapeutic Agents; Thermodynamics; Time; Work; Yeasts; design; directed evolution; insight; interdisciplinary approach; interest; novel therapeutics; protein function; public health relevance; receptor; receptor function; tool

DESCRIPTION (provided by applicant): The goal of this project is to understand protein evolution at the molecular level. An interdisciplinary approach will be taken that combines the strengths of evolutionary biology and molecular biophysics. As proteins evolve, they must maintain function or they will be removed by selection. Recent investigations using ancestral protein resurrection have found functional intermediates in the evolution of the medically important steroid receptor (SR) proteins. The mutational pathway connecting different functional states is characterized by strong sign epistasis: "permissive" mutations must precede "function-switching" mutations to maintain function along the evolutionary trajectory. The mechanism of these permissive mutations is not well understood. This project will use the methods of biophysics and directed evolution to determine the mechanisms of these historical permissive mutations. The first aim of the project is to probe the relationship between protein stability and evolution. The second aim is to understand the role of contingency in the evolution of complex protein function. This work has important implications for understanding the general principles of protein evolution. It will also provide insight into the molecular determinants of ligand specificity in SRs, which will inform attempts to create novel therapeutic agents that modulate SR function. PUBLIC HEALTH RELEVANCE: Steroid receptors-which are key players in diseases ranging from asthma to cancer-must discriminate between similar hormones to function properly. Like all proteins, their ability to perform this function is a product of their evolutionary history. This project attempts to understand how this function evolved, which will potentially allow for new drugs to modulate steroid receptor function to treat disease.

描述（由申请人提供）：该项目的目标是在分子水平上了解蛋白质的进化。将采取跨学科方法，结合进化生物学和分子生物物理学的优势。随着蛋白质的进化，它们必须保持功能，否则就会被选择去除。最近利用祖先蛋白复活进行的研究发现了医学上重要的类固醇受体（SR）蛋白进化过程中的功能中间体。连接不同功能状态的突变途径具有很强的符号上位性：“允许”突变必须先于“功能转换”突变才能沿着进化轨迹维持功能。这些允许突变的机制尚不清楚。该项目将利用生物物理学和定向进化的方法来确定这些历史允许突变的机制。该项目的首要目标是探讨蛋白质稳定性与进化之间的关系。第二个目标是了解偶然事件在复杂蛋白质功能进化中的作用。这项工作对于理解蛋白质进化的一般原理具有重要意义。它还将提供对 SR 配体特异性的分子决定因素的深入了解，这将为创造调节 SR 功能的新型治疗剂的尝试提供信息。 公共健康相关性：类固醇受体是从哮喘到癌症等疾病的关键参与者，必须区分相似的激素才能正常发挥作用。与所有蛋白质一样，它们执行此功能的能力是其进化历史的产物。该项目试图了解这种功能是如何进化的，这将有可能允许新药调节类固醇受体功能来治疗疾病。