Tethered Domains As Regulatory Elements

描述（由申请人提供）：我们的工作有助于发现ACT结构域（一种由小分子调节的蛋白质调节结构域），并产生了原型ACT结构域的结构。本研究的目的是继续我们对ACT结构域调节蛋白质的机制的研究，并将其与本实验室的长期目标联系起来，该长期目标是确定构象调节控制机制中结构和功能之间的关系，最终将其与这些酶和类似系统介导的生理学和病理生理学联系起来，并最终充分理解蛋白质中构象介导的过程，以便能够将基本原理应用于更复杂的系统。具体的目的是：1）阐明大肠杆菌D-3-磷酸甘油酸脱氢酶（PGDN）ACT结构域的作用机制; coli和M.结核分枝杆菌中发现的一个新的结构域和小分子结合位点的功能。结核分枝杆菌PGDH可能与ACT结构域一起发挥作用，3）确定人PGDH的结构和功能，和4）筛选M的配体结合位点。结核病PGDH的抑制剂的发展，可用于评估PGDH的作用，在代谢的M。本发明的组合物可用于治疗活动期、适应期和持续期的结核病，并且最终可用于治疗耐多药结核病。这项工作的相关性是双重的。首先，ACT结构域是一个新认识的结构域，在许多蛋白质的调节中发挥作用。确定其作用机制及其在蛋白质间作用的普遍性，将有助于我们对生理和疾病中蛋白质调控的理解，并为基因替代治疗中的蛋白质调控提供潜在的新武器。第二，耐多药结核病是一个日益严重的问题，影响到世界上很大一部分人口。我们观察到M.结核病被L-丝氨酸抑制，而人PGDH不被抑制，这可能为治疗结核病的药物开发提供新的焦点。

DESCRIPTION (provided by applicant): Our work has contributed to the discovery of the ACT domain, a protein regulatory domain modulated by small molecules, and has produced the structure of the archetypical ACT domain. The goal of this research is to continue our investigation into the mechanism of regulation of proteins by the ACT domain and to relate this to the long term goals of this laboratory which are to determine the relationship between structure and function in conformationally regulated control mechanisms, to eventually relate that to the physiology and pathophysiology mediated by these enzymes and by analogous systems, and to eventually understand conformational mediated processes in proteins well enough to be able to apply basic principles to more complex systems. The specific aims will 1) elucidate the mechanism of the ACT domain in D-3- phosphoglycerate dehydrogenase (PGDN) from E. coli and M. tuberculosis, 2) elucidate the function of a new structural domain and small molecule binding site found in M. tuberculosis PGDH that may function in conjunction with the ACT domain, 3) determine the structure and function of human PGDH, and 4) screen the ligand binding sites of M. tuberculosis PGDH for the development of inhibitors that can be used to assess the role of PGDH in the metabolism of M. tuberculosis during its active, adaptive and persistent phases and that may eventually be used for the treatment of multi-drug resistant tuberculosis. The relevance of this work is 2-fold. First, the ACT domain is a newly recognized structural domain that functions in the regulation of many proteins. Determining its mechanism and the universality of its action among proteins will contribute to our understanding of protein regulation in physiology and disease as well as provide a potential new weapon for protein regulation in gene replacement therapy. Secondly, multi-drug resistant tuberculosis is a growing problem that impacts a large percentage of the world's population. Our observations that PGDH from M. tuberculosis is inhibited by L-serine and that PGDH from humans is not, may provide a new focus in drug development for treatment of tuberculosis.