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Deciphering GPCR signal transduction through NMR structure and dynamics studies

通过 NMR 结构和动力学研究破译 GPCR 信号转导

基本信息

批准号：
9135502
负责人：
Joshua James Ziarek
金额：
$ 9万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9135502
关键词：
Adrenergic Receptor Agonist Amino Acids Applied Research Area Arrestins Basic Science Binding Biochemical Biochemistry Boston Cells Chemicals Chemistry Chimeric Proteins Codon Nucleotides Communities Complex Comprehension Data Analyses Data Collection Development Diphosphates Directed Molecular Evolution Discipline Disease Environment Escherichia coli Faculty Funding G Protein-Coupled Receptor Signaling G protein coupled receptor kinase G-Protein-Coupled Receptors G-substrate GTP-Binding Proteins Gatekeeping Gene Silencing Guanosine Triphosphate Health Heterotrimeric GTP-Binding Proteins Human Insecta Institutes Isotope Labeling Label Laboratories Laboratory Research Lead Length Ligand Binding Ligands Marketing Mass Spectrum Analysis Measures Membrane Proteins Mentors Methods Molecular Biology Monitor Motion Muramidase Mutation NMR Spectroscopy Neurotensin Neurotensin Receptors Nucleotides Outcome Pattern Pharmaceutical Preparations Phase Phosphopeptides Phosphorylation Phosphotransferases Physics Protein Biochemistry Protein Family Protein Kinase C Proteins Proteome Public Health Reaction Receptor Activation Research Role Scheme Scientist Serine Signal Pathway Signal Transduction Social Sciences Specificity Structure Surface System Techniques Technology Testing Threonine Training Translating United States National Institutes of Health Universities Work X-Ray Crystallography analog arrestin 1 arrestin 2 base drug discovery empowered extracellular flexibility human disease insight interest macromolecule medical schools member milligram millisecond molecular recognition nanobodies nanodisk nanosecond professor programs protein complex receptor receptor structure function receptor-mediated signaling research study sortase structural biology theories

项目摘要

DESCRIPTION (provided by applicant): G protein-coupled receptors (GPCRs) are critical eukaryotic signal transduction gatekeepers and represent the largest protein family in the human proteome, with more than 800 members. In recent years, X-ray crystallography has yielded many G protein-coupled receptor structures but the mechanism of allosteric signaling remains unknown. X-ray crystallography of GPCRs requires multiple forms of receptor stabilization that, subsequently, limit conformational dynamics. RESEARCH: Directed evolution of GPCRs enables milligram quantities of functional, isotopically-labeled protein to be produced from prokaryotic expression systems. This technology opens the field for NMR studies of GPCRs with various ligands and in complex with G proteins and arrestins. Focusing on the neurotensin receptor, the PI will use NMR spectroscopy to probe the structure and conformational dynamics of GPCR activation in solution. TRAINING: The proposed training in Professor Wagner's laboratory at Harvard Medical School will solidify the PI's comprehension of NMR theory and implementation. In addition to advanced NMR techniques, the PI will acquire a thorough understanding of membrane protein biochemistry, nanodiscs, and directed evolution. Together, these techniques will empower the PI to establish an independent, NIH-funded structural biology research program. ENVIRONMENT: Professor Gerhard Wagner's laboratory at Harvard University Medical School presents the optimal environment for this project. His work has been integral to the development of multidimensional NMR experiments for biomolecule characterization; in particular, Dr. Wagner is a leader in data collection and analysis of large macromolecules. Harvard Medical School has nearly 8,000 faculty and 17 affiliated facilities. At the core of the Medical School are its educational and research programs. The Medical School has nine departments in basic and social science disciplines. The wider Boston/Cambridge area contains numerous research laboratories including MIT, Whitehead, and Broad Institutes with interests in structural biology, biochemistry, molecular biology, chemistry and physics, with scientists interested in the general themes related to this proposal. IMPACT ON PUBLIC HEALTH: GPCR-mediated signaling pathways have been related to numerous human diseases, and GPCRs are the targets of an estimated 30-40% of all drugs currently on the market. In view of their fundamental roles in health and disease, a detailed understanding of GPCR structure and function is of value to the basic science community interested in cell signaling and molecular recognition, as well as to the applied science community interested in drug discovery.