Structure and Function of the ATP synthase

ATP合酶的结构和功能

• 批准号: 9304243
• 负责人: David Michael Mueller
• 金额: $ 47.46万
• 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 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9304243
• 关键词: ATP Hydrolysis; ATP Synthesis Pathway; Aerobic; Affect; Automobile Driving; Biochemical; Biochemistry; Biological Process; Complex; Coupled; Coupling; Cryoelectron Microscopy; Crystallization; Crystallography; Data Set; Disease; Enzymes; Event; Genes; Genetic Engineering; Genetic Variation; Genomics; Goals; Health; Healthcare; Human; Ions; Knowledge; Mediating; Mitochondria; Mitochondrial Diseases; Mitochondrial Proton-Translocating ATPases; Molecular; Molecular Conformation; Molecular Weight; Multienzyme Complexes; Mutagenesis; Mutation; Pathway interactions; Phenotype; Population; Positioning Attribute; Property; Protons; Reaction; Resolution; Rotation; Single Nucleotide Polymorphism; Structure; Testing; Translations; Variant; X ray diffraction analysis; X-Ray Diffraction; Yeasts; disease-causing mutation; improved; inhibitor/antagonist; knowledge base; mitochondrial membrane; mutant; particle; protein complex; public health relevance; synchrotron radiation; x-ray free-electron laser

 DESCRIPTION (provided by applicant): The mitochondrial F1Fo ATP synthase is responsible for the synthesis 90% of the ATP under aerobic conditions. The mitochondrial ATP synthase is a multimeric protein complex with an overall molecular weight greater than 550,000 Da. A portion of the ATP synthase is embedded in the mitochondrial membrane and acts as a proton turbine and a portion is in the matrix space and acts as a rotary engine that phosphorylates ADP. Despite many people*decades devoted across the globe, the structure of the entire enzyme complex has remained elusive. Because of recent technological advances and progress, we are now on the brink of obtaining the high-resolution structure of the mitochondrial enzyme. One key unanswered question is: what are the molecular determinants that cause the central stalk to rotate during ATP synthesis and hydrolysis? A principal goal of this project is to determine the high-resolution crystal structure of the eukaryotic ATP synthase complex. This aim will give critical structural details into the understanding of the mechanism of proton translocation coupled to rotation driving ATP synthesis or driven by ATP hydrolysis. We will investigate the structural relationship of the ATP synthase in a number of reaction intermediate structures with inhibitors bound. We will exploit our understanding of the structure and biochemistry of the ATP synthase and aim to gain a further understanding of human mitochondrial diseases and variations amongst the population. This study will help bridge the knowledge gap between the genomic studies and biochemistry and will allow for translation into healthcare. Overall, the project will provide basic understanding on the mechanism of proton translocation coupled to an energy-requiring event - the synthesis of ATP from ADP and Pi - and aid in knowledge-based decisions in both the health and disease.

 描述（由申请人提供）：线粒体F1 Fo ATP合酶负责在有氧条件下合成90%的ATP。线粒体ATP合酶是总分子量大于550，000 Da的多聚体蛋白复合物。ATP合酶的一部分嵌入线粒体膜中并充当质子涡轮机，一部分位于基质空间中并充当磷酸化ADP的旋转发动机。尽管许多人在地球仪上花费了几十年的时间，整个酶复合物的结构仍然难以捉摸。由于最近的技术进步和进步，我们现在即将获得线粒体酶的高分辨率结构。一个关键的问题是：在ATP合成和水解过程中，是什么分子决定因素导致中心柄旋转？该项目的主要目标是 确定真核ATP合酶复合物的高分辨率晶体结构。这一目标将提供关键的结构细节，以了解质子易位耦合到旋转驱动ATP合成或驱动ATP水解的机制。我们将研究ATP合酶在许多反应中间体结构中与抑制剂结合的结构关系。我们将利用我们对ATP合酶的结构和生物化学的理解，旨在进一步了解人类线粒体疾病和人群中的变化。这项研究将有助于弥合基因组研究和生物化学之间的知识差距，并将允许转化为医疗保健。总的来说，该项目将提供对质子易位机制的基本了解，该机制与能量需求事件相结合-从ADP和Pi合成ATP-并帮助健康和疾病中基于知识的决策。