Paragons of Conformational Control in Metalloenzyme Reactivity

金属酶反应性构象控制的典范

• 批准号: 10221737
• 负责人: Lisa Olshansky
• 金额: $ 38.61万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10221737
• 关键词: Active Sites; Anabolism; Binding; Biochemical; Biochemistry; Biology; Biophysics; Catalysis; Chemistry; Complex; Development; Drug Delivery Systems; Drug Targeting; Elements; Entropy; Environment; Enzymes; Event; Functional disorder; Health; Human; Kinetics; Link; Maintenance; Metalloproteins; Methods; Mitochondria; Modeling; Molecular Conformation; Nature; Oxidation-Reduction; Play; Proteins; Regulation; Research; Respiration; Role; Sampling; Structure; System; Thermodynamics; Time; Work; bioimaging; catalyst; cost; metal complex; metalloenzyme; paragon; respiratory protein

Paragons of Conformational Control in Metalloenzyme Reactivity Lisa Olshansky Project Summary. Recent decades have witnessed a revolution in what was once a static picture of biology. For example, the tenets of biochemistry once taught that sequence determines structure, but we now know that sequence and cellular environment determine conformational sampling. Evolutionary selection acts on dynamic rather than static features. The implications for this dynamic biochemical world permeate all aspects of human health. Therefore, it is essential that contemporary research explore the roles, mechanisms, and structure- function paradigms at play therein. However, the complex interplay between structural changes and changes in reactivity make exploring these paradigms in natural systems incredibly challenging. At the same time, simplified synthetic models typically fail to capture the key elements of control leveraged in Nature to regulate activity. My approach is to combine these tactics. By incorporating synthetically prepared metal complexes into proteins that have evolved to undergo allosterically driven conformational changes, we are preparing switchable artificial metalloproteins (swArMs) that represent paragons for conformational control in metalloenzyme reactivity. By creating artificial systems in which changes in structure are directly linked to changes in function, we aim to quantify the effects of conformational control in terms of thermodynamic and kinetic parameters underlying reactivity. Ultimately, this understanding can be harnessed in the development of new catalysts, bioimaging agents, and systems for targeted drug delivery. Our work is poised for the exploration of key unanswered questions in enzyme catalysis, such as how allosteric binding events are converted into metallocofactor activation, or how entropic factors regulate radical chemistry, or how energy conversion occurs in mitochondrial respiratory proteins. Using a wide range of biophysical and spectroscopic methods, swArMs provide a platform with which to explore all of these questions, and to examine the mechanisms of regulation underlying function and dysfunction in metalloenzyme reactivity that are critical to human health.

金属酶反应的构象控制典范丽莎·奥尔尚斯基 项目摘要。近几十年来，曾经是静态的生物学图景发生了一场革命。 例如，生物化学的原理曾经教导说，序列决定结构，但我们现在知道 序列和细胞环境决定了构象采样。进化选择作用于动态 而不是静态特征。对这个动态的生化世界的影响渗透到人类的方方面面 健康。因此，当代研究必须探索角色、机制和结构-- 函数范例在其中发挥作用。然而，结构变化和经济结构变化之间的复杂相互作用 反应性使得在自然系统中探索这些范例具有难以置信的挑战性。同时，简化了 合成模型通常无法捕捉到自然界用来调节活动的控制的关键要素。我的 方法是将这些战术结合起来。通过将合成的金属络合物结合到蛋白质中， 已经进化到经历变构驱动的构象变化，我们正在准备可切换的人工 金属蛋白(群)，代表在金属酶反应中进行构象控制的典范。通过 创建结构变化与功能变化直接相关的人工系统，我们的目标是 根据热力学和动力学参数量化构象控制的影响 反应性。最终，这种理解可以被用于开发新的催化剂、生物成像 用于靶向药物输送的试剂和系统。我们的工作正准备探索未回答的关键 酶催化中的问题，如变构结合事件如何转化为金属辅因子 激活，或熵因素如何调节自由基化学，或线粒体如何发生能量转换 呼吸蛋白。利用广泛的生物物理和光谱方法，蜂群提供了一个平台 用它来探索所有这些问题，并检查潜在的调节功能的机制 以及对人类健康至关重要的金属酶反应功能障碍。