Allosteric Regulation of Proteins involved in Phosporylation-based signaling

参与基于磷酸化的信号传导的蛋白质的变构调节

• 批准号: 10244671
• 负责人: Lalima Katyayani Madan
• 金额: $ 23.28万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 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 2022-01-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10244671
• 关键词: Active Sites; Allosteric Regulation; Catalytic Domain; Cells; Centers of Research Excellence; Charge; Communities; Complex; Cyclic AMP-Dependent Protein Kinases; Disease; Drug Targeting; Enzymes; Equilibrium; Event; Family; Frequencies; Maps; Modeling; Molecular; Mutation; Oxidants; Oxidation-Reduction; PARD6A gene; Pharmacologic Substance; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Physiological; Post-Translational Protein Processing; Protein Dynamics; Protein Footprinting; Protein Kinase; Protein Tyrosine Phosphatase; Protein phosphatase; Proteins; Regulation; Role; Signal Transduction; South Carolina; Stress; Structure; Study models; Surface; Tertiary Protein Structure; Work; base; drug discovery; enzyme activity; graph theory; inorganic phosphate; novel; protein complex; protein protein interaction; receptor; string theory

Protein Phosphorylation is a key post-translational modification that allows for physiologically relevant signaling cascades in the cell. These phosphorylation events alter surface charges of protein thus allowing for modulation of protein-protein interactions relevant to the needs of the cell. Molecular enzymes that direct protein phosphorylation are essentially protein kinases (that phosphorylate proteins using ATP) and protein phosphatases (that remove these phosphates from proteins). A delicate balance between the opposing activities of these enzymes maintains critical signaling events in the cell. Evidently, both protein kinases and protein phosphatases are critical pharmaceutical targets for drug discovery. High conservation of the catalytic domains of these proteins and their conserved active site mechanisms continue to challenge the field that works towards targeting specific kinases or phosphatases implicated in specialized disease states. In the past decade, allosteric modulation and harmonic models of protein dynamics has gathered momentum. The present proposal combines these two aspects of protein regulation and attempts to look at dynamics-based allostery in protein kinases, phosphatases and their pseudo-enzyme forms. The proposal develops of the principals of 'String Theory' and seeks to conceptualize the energy-frequency mode of these enzymes using the Violin model of allostery. Essentially, all harmonic frequencies of the internal dynamics of these proteins are used to define their catalytic states in the form of a graph theory based community map. These maps are then used to study specific mutation states or protein complexes to decipher the roles of these allosteric modulators on the function of these enzymes.

蛋白质磷酸化是一种关键的翻译后修饰，它允许细胞中与生理相关的信号级联反应。这些磷酸化事件改变了蛋白质的表面电荷，从而允许调节与细胞需求相关的蛋白质-蛋白质相互作用。指导蛋白质磷酸化的分子酶本质上是蛋白质激酶(使用三磷酸腺苷使蛋白质磷酸化)和蛋白质磷酸酶(从蛋白质中去除这些磷酸盐)。这些酶的相对活性之间的微妙平衡维持着细胞中的关键信号事件。显然，蛋白激酶和蛋白磷酸酶都是药物发现的关键药物靶点。这些蛋白质的催化域及其保守的活性部位机制的高度保守继续挑战着靶向特定疾病状态中涉及的特定激酶或磷酸酶的领域。在过去的十年里，蛋白质动力学的变构调节和调和模型获得了发展势头。本提案结合了蛋白质调节的这两个方面，并试图研究蛋白质激酶、磷酸酶及其假酶形式中的基于动力学的变构。该提议发展了弦理论的原理，并试图用小提琴来概念化这些酶的能量-频率模式 变构模型。本质上，这些蛋白质内部动力学的所有谐波频率都被用来以基于图论的社区地图的形式来定义它们的催化状态。这些地图然后被用来研究特定的 突变状态或蛋白质复合体，以破译这些变构调节剂对这些酶功能的作用。