Tethered Domains As Regulatory Elements

受限域作为监管要素

• 批准号: 7449657
• 负责人: GREGORY A GRANT
• 金额: $ 34.29万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-01-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7449657
• 关键词: Active Sites; Allosteric Regulation; Amino Acids; Binding Sites; Characteristics; Chemicals; Complex; Development; Dihydrofolate Reductase; Disease; Elements; Enzymes; Escherichia coli; Functional disorder; Goals; Grant; Human; Infection; Investigation; Ions; Knowledge; Laboratories; Ligand Binding; Mediating; Metabolic Control; Metabolism; Metals; Multidrug-Resistant Tuberculosis; Mycobacterium tuberculosis; Pathway interactions; Pharmaceutical Preparations; Phase; Phosphoglycerate dehydrogenase; Physiology; Population; Process; Protein Kinase; Proteins; Regulation; Regulatory Element; Replacement Therapy; Research; Role; Serine; Site; Specificity; Structure; Structure-Activity Relationship; System; Tuberculosis; Vitamins; Work; drug development; gene replacement; genetic regulatory protein; inhibitor/antagonist; knowledge base; novel; numb protein; prototype; small molecule; tuberculosis treatment

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.

描述（由申请人提供）：我们的工作有助于发现ACT结构域，ACT结构域是由小分子调节的蛋白质调节结构域，并产生了原型ACT域的结构。这项研究的目的是继续我们对ACT领域调节蛋白质调节机制的调查，并将其与该实验室的长期目标联系起来，这些目标是确定结构和功能在受构象控制的控制机制中的关系，以最终将其与这些酶的概念构成的概念相关，并最终与这些酶的概念相关，并以类似的概括为构成的概括，并与之相关。更复杂的系统的原理。具体目的将1）阐明来自大肠杆菌和结核分枝杆菌的D-3-磷酸甘油酸脱氢酶（PGDN）中ACT结构域的机制，2）阐明了新的结构结构域和小分子结合位点的功能，在M. pgdh中发现了在conjuntion和conjuntion中的作用。结核分枝杆菌PGDH的配体结合位点用于开发抑制剂，这些抑制剂可用于评估PGDH在结核分枝杆菌的代谢中的作用，并在其活性，适应性和持久阶段，最终可用于治疗多药耐药性结核病。这项工作的相关性是2倍。首先，该ACT结构域是一个新认识的结构结构域，可在许多蛋白质的调节中起作用。确定其机制及其在蛋白质中的作用的普遍性将有助于我们对生理和疾病中蛋白质调节的理解，并为基因替代治疗中的蛋白质调节提供潜在的新武器。其次，多药耐药性结核病是一个日益严重的问题，影响了世界人口的很大一部分。我们的观察结果是，L-塞罗抑制了结核分枝杆菌的PGDH，而不是人类的PGDH，可能为治疗结核病的药物开发提供了新的重点。