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F1Fo ATP合酶负责在有氧条件下合成90%的ATP。线粒体 ATP 合酶是一种多聚体蛋白质复合物，总分子量大于 550,000 Da。 ATP 合酶的一部分嵌入线粒体膜中，充当质子涡轮，一部分位于基质空间中，充当磷酸化 ADP 的旋转发动机。尽管全球许多人投入了数十年的努力，但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。一个尚未解答的关键问题是：在 ATP 合成和水解过程中导致中心茎旋转的分子决定因素是什么？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。这一目标将为理解质子易位与驱动 ATP 合成或由 ATP 水解驱动的旋转耦合的机制提供关键的结构细节。我们将研究 ATP 合酶在许多与抑制剂结合的反应中间体结构中的结构关系。我们将利用对 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，并将其转化为医疗保健领域。总体而言，该项目将提供对质子易位与能量需求事件（从 ADP 和 Pi 合成 ATP）相结合的机制的基本了解，并有助于健康和疾病方面的基于知识的决策。