Structure and Function of the Yeast ATPase

酵母 ATP 酶的结构和功能

基本信息

批准号：
7766686
负责人：
David Michael Mueller
金额：
$ 1.12万
依托单位：
ROSALIND FRANKLIN UNIV OF MEDICINE & SCI
依托单位国家：
美国
项目类别：
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/7766686
关键词：
ATP Synthesis Pathway ATP phosphohydrolase Address Aerobic Antibiotics Apoptosis Area Bacteria Bacterial Infections Berry Biochemical Biological Assay Caloric Restriction Cells Collaborations 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 Obesity Pharmaceutical Preparations Process Property Proteins Protons Pseudomonas aeruginosa 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

项目摘要

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（申请人提供）：线粒体ATP合酶负责在有氧条件下真核细胞中90%以上的细胞ATP的合成。 ATP 是细胞用于几乎所有需要能量的过程（例如肌肉收缩（如心脏）和生物合成反应）的能量货币。这是对该酶进行深入研究的主要推动力。但最近的研究揭示了研究 ATP 合酶的更大理由。 ATP 合酶涉及许多其他与 ATP 合成活性相关或无关的关键过程。 ATP合酶是潜在的靶标，可以通过引发细胞凋亡或调节血管生成来治疗癌症，治疗狼疮，通过增加代谢率从而提供热量限制或通过调节参与延长寿命的已知受体来延长人类的寿命-跨度，预防心脏病，治疗眼部疾病，例如青光眼或黄斑变性，治疗肥胖，以及治疗细菌感染，例如由结核分枝杆菌或机会性致病菌引起的感染细菌，铜绿假单胞菌。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，如果这些区域受到调节，则会失活或损害该酶。长期目标是针对这些区域进行合理的药物设计，以确定新的抗生素或药物。该项目有两个目标。第一个目标是识别和理解对于质子流与线粒体 ATP 合酶合成 ATP 的耦合至关重要的分子结构特征。第二个目标是确定 ATP 合酶中的潜在靶标，以进行合理的药物设计。这些目标将通过同一组实验来实现。具体来说，将在γ-亚基内或与γ-亚基相关的区域进行鉴定，这些区域具有严格的结构要求，如果受到干扰，则会降低 ATP 合酶的偶联效率。该分析将使用基于结构的诱变研究进行，随后对突变蛋白进行生化和生物物理分析，并通过 ATP 合酶的结构测定。未来的研究将针对这些区域开发抗生素，这些抗生素要么扰乱耦合效率，要么阻止病原菌 ATP 合酶 γ 亚基的旋转。