The role of conformationally plastic loops in enzyme function, stability and regulation

以蛋白质为基础的催化剂，也就是酶，对地球上的所有生命都至关重要。由此可见，了解酶是如何进行它们所介导的化学转化的，是基本了解生命的关键。此外，改变或改造酶功能的能力将为生物技术开辟新的途径，例如开发新型生物燃料和生产治疗感染和疾病的新药。为了使这些想法成为现实，我们对酶如何作为高效和选择性的生物催化剂发挥作用有一个深入和基本的了解是至关重要的。为了实现这一目标，最近的研究表明，酶是灵活的分子，并且在溶液中以相互转换的构象状态的群体存在，这些构象波动对酶的正常功能至关重要。现在这种现象已经被确定，我们的目标是了解酶的这种构象灵活性是如何与酶的正常功能联系在一起的。为了帮助理解构象柔韧性如何影响酶的功能，我们将研究酶柔韧性在磷酸烯醇丙酮酸羧激酶家族中的作用。通过这一研究项目，我们将更好地了解作为酶结构一部分的环元件的构象转变对催化功能、酶稳定性和活性调节的必要性，并通过分析来自不同物种的该家族的酶来研究蛋白质结构中可移动元件的结构约束。

Protein based catalysts, known as enzymes, are essential to all life on earth. It follows that understanding how enzymes carry out the chemical transformations they mediate is key to a basic understanding of life. In addition, the ability to alter or engineer enzyme function will open up new avenues in biotechnology such as the development of novel biofuels and the generation of new pharmaceuticals to treat infection and disease. For these ideas to become a reality it is of paramount importance that we have an intimate and fundamental understanding of how enzymes function as efficient and selective biological catalysts. Working towards this goal, recent studies have demonstrated that enzymes are flexible molecules and exist in solution as a population of interconverting conformational states and that these conformational fluctuations are vitally important to proper enzyme function. Now that this phenomenon has been identified, it is our goal to understand how this conformational flexibility of enzymes is tied to the ability of the enzyme to function correctly. To help develop this understanding of how conformational flexibility impacts enzyme function, we will investigate the role of enzyme flexibility in the family of enzymes identified as phosphoenolpyruvate carboxykinases. Through this program of research, we will develop a better picture of how conformational transitions in loop elements that are part of the enzyme's structure are necessary for catalytic function, enzyme stability, and regulation of activity as well as investigate the structural constraints on mobile elements of protein structure through analysis of enzymes in this family from diverse species.