Structure and Function of the Yeast ATPase

酵母 ATP 酶的结构和功能

• 批准号: 7392837
• 负责人: David Michael Mueller
• 金额: $ 27.11万
• 依托单位: ROSALIND FRANKLIN UNIV OF MEDICINE & SCI
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7392837
• 关键词: ATP Synthesis Pathway; ATP phosphohydrolase; Address; Aerobic; Antibiotics; Apoptosis; Area; Bacteria; Bacterial Infections; Berry; Biochemical; Biological Assay; Caloric Restriction; Cells; Collaborations; Condition; Coupling; Crystallization; Development; Drug Design; Enzymes; Eukaryotic Cell; Eye diseases; F1-ATPase; Funding; Future; Glaucoma; Goals; Heart; Heart Diseases; Human; Life; Longevity; Lupus; Macular degeneration; Malignant Neoplasms; Measures; Metabolic; Mitochondria; Mitochondrial Proton-Translocating ATPases; Molecular; Muscle Contraction; Mutagenesis; Mutation; Mycobacterium tuberculosis; Numbers; Obesity; Pharmaceutical Preparations; Process; Property; Proteins; Protons; Pseudomonas aeruginosa; Rate; Reaction; Role; Rotation; Speed; Structure; Structure-Activity Relationship; Time; Torque; Yeasts; angiogenesis; base; insight; laser tweezer; mutant; optical traps; pathogenic bacteria; prevent; protein structure; receptor; research study; single molecule

DESCRIPTION (provided by applicant): The mitochondrial ATP synthase is responsible for the synthesis of more than 90% of cellular ATP in the eukaryotic cell under aerobic conditions. ATP is the energy currency that the cell uses for nearly all energy requiring processes such as muscle contraction (as in the heart) and biosynthetic reactions. This has been a major impetus for the intense studies on this enzyme. But recent studies have revealed even greater cause to study the ATP synthase. The ATP synthase has been implicated in a number of other critical processes that are either related or unrelated to the activity of synthesis of ATP. The ATP synthase is a potential target to cure cancer either by eliciting apoptosis or by modulating angiogenesis, to treat Lupus, to extend the life- time of humans either by increasing the metabolic rate thereby providing caloric restriction or by modulating known receptors involved in extended life-span, to prevent heart disease, to treat eye disease, such as glaucoma or macular degeneration, to treat obesity, and to treat bacterial infections such as those caused by Mycobacterium tuberculosis or the opportunistic bacterium, Pseudomonas aeruginosa. The immediate goal of this project is to understand the structure/function relationship of the ATP synthase and to identify critical structural regions of the ATP synthase, which if modulated, inactivate or impair the enzyme. The long-term goal is to target these regions for rational drug design to identify new antibiotics or drugs. There are two objectives for this project. The first objective is to identify and understand molecular structural features critical for the coupling of the flow of protons with the synthesis of ATP by the mitochondrial ATP synthase. The second objective is to identify potential targets in the ATP synthase for rational based drug design. These objectives will be obtained with the same set of experiments. Specifically, regions will be identified within, or associated with, the gamma-subunit, which have strict structural requirements and if perturbed, reduces the efficiency of the coupling of the ATP synthase. This analysis will be done using structure-based mutagenesis studies followed by biochemical and biophysical analysis of the mutant proteins and by structure determination of the ATP synthase. Future studies will target these regions for the development of antibiotics, which either perturb the coupling efficiency or block rotation of the gamma-subunit of the ATP synthase from pathogenic bacteria.

描述（由申请人提供）：在有氧条件下，线粒体ATP合酶负责真核细胞中超过90％的细胞ATP合成。 ATP是细胞用于几乎所有需要肌肉收缩（如心脏）和生物合成反应等过程的能量的能源货币。这是对该酶进行激烈研究的主要动力。但是最近的研究揭示了更大的理由研究ATP合酶。 ATP合酶已与许多与ATP合成活性相关或无关的许多其他关键过程。 ATP合酶是通过引起凋亡或通过调节血管生成，治疗狼疮，以增加代谢率来延长人类寿命的潜在靶标，可以通过增加热量限制或通过调节涉及的已知受体来延长人类的寿命，以治疗刺激性刺激性，以治疗心脏病，以治疗刺激性虫病，或治疗刺激性疾病，或者诸如结核分枝杆菌或机会性细菌铜绿假单胞菌引起的感染。该项目的直接目标是了解ATP合酶的结构/功能关系，并确定ATP合酶的关键结构区域，如果调节，灭活或损害酶。长期目标是针对这些区域进行理性药物设计，以鉴定新的抗生素或药物。这个项目有两个目标。第一个目的是识别和理解分子结构特征对于质子流动与线粒体ATP合酶合成ATP的偶联至关重要的分子结构特征。第二个目标是确定基于理性药物设计的ATP合酶中的潜在靶标。这些目标将通过相同的一组实验获得。具体而言，将在具有严格的结构要求的伽马亚基中或与伽马亚基相关联，如果受到干扰，则会降低ATP合酶偶联的效率。该分析将使用基于结构的诱变研究进行，然后对突变蛋白和ATP合酶的结构测定进行生化和生物物理分析。未来的研究将以这些区域的形式开发抗生素，这要么扰动致病细菌的ATP合酶的γ-亚基的耦合效率或阻滞旋转。