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.