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(申请人提供)：线粒体F1Fo ATP合成酶负责在有氧条件下合成90%的ATP。线粒体ATP合成酶是一种总分子量大于550,000 Da的多聚体蛋白质复合体。ATP合成酶的一部分嵌入线粒体膜，充当质子涡轮机，一部分嵌入基质空间，充当使ADP磷酸化的旋转引擎。尽管许多人在全球投入了几十年的时间，整个酶复合体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。一个关键的悬而未决的问题是：在ATP合成和水解过程中，导致中央茎旋转的分子决定因素是什么？这个项目的一个主要目标是 确定真核细胞三磷酸腺苷合成酶复合体的高分辨晶体结构。这一目标将提供关键的结构细节，以理解质子转运与旋转耦合驱动ATP合成或由ATP水解驱动的机制。我们将研究与抑制剂结合的一些反应中间结构中三磷酸腺苷合成酶的结构关系。我们将利用我们对ATP合成酶的结构和生物化学的了解，目的是进一步了解人类线粒体疾病和种群中的变异。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，并将允许将其转化为医疗保健。总体而言，该项目将提供关于质子转移与需要能量的事件-从ADP和PI合成ATP-的机制的基本理解，并帮助做出健康和疾病方面的基于知识的决策。