Molecular Mechanisms of the Evolution of Steroid Receptor-Ligand Interactions

描述（由申请人提供）：该项目的目标是在分子水平上理解蛋白质的进化。将采取跨学科的方法，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，否则就会被选择所淘汰。最近使用祖先蛋白复活的研究发现了在医学上重要的类固醇受体（SR）蛋白进化中的功能中间体。连接不同功能状态的突变途径以强符号上位为特征：“允许”突变必须先于“功能切换”突变，以维持进化轨迹上的功能。这些允许突变的机制尚不清楚。该项目将使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。该项目的第一个目标是探索蛋白质稳定性和进化之间的关系。第二个目标是了解偶然性在复杂蛋白质功能进化中的作用。这项工作对理解蛋白质进化的一般原理具有重要意义。它还将深入了解SR中配体特异性的分子决定因素，这将为创建调节SR功能的新型治疗剂提供信息。

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.