Allosteric Regulation of Proteins involved in Phosporylation-based signaling

蛋白质磷酸化是一种关键的翻译后修饰，允许细胞中生理相关的信号级联。这些磷酸化事件改变蛋白质的表面电荷，从而允许调节与细胞需要相关的蛋白质-蛋白质相互作用。指导蛋白质磷酸化的分子酶基本上是蛋白激酶（使用ATP使蛋白质磷酸化）和蛋白磷酸酶（从蛋白质中除去这些磷酸盐）。这些酶的相反活性之间的微妙平衡维持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标。这些蛋白质的催化结构域的高度保守性及其保守的活性位点机制继续挑战致力于靶向与特定疾病状态有关的特定激酶或磷酸酶的领域。在过去的十年中，蛋白质动力学的变构调节和谐波模型已经聚集了动力。目前的建议结合了这两个方面的蛋白质调控，并试图在蛋白激酶，磷酸酶和它们的假酶形式的动力学为基础的变构。该提案发展了“弦理论”的原则，并试图用小提琴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用于以基于图论的社区地图的形式定义其催化状态。这些地图被用来研究特定的 突变状态或蛋白质复合物来破译这些变构调节剂对这些酶的功能的作用。

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.