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Quantitative analysis of metabotropic glutamate receptor activation and modulation

代谢型谷氨酸受体激活和调节的定量分析

基本信息

批准号：
10463681
负责人：
Reza Vafabakhsh
金额：
$ 33.25万
依托单位：
NORTHWESTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10463681
关键词：
Affect Allosteric Regulation Anxiety Architecture Binding Sites Biochemical Biological Biological Assay Biophysics Brain Calcium-Sensing Receptors Cell membrane Cells Chemicals Cholesterol Complement Complex Computing Methodologies Coupled Coupling Cysteine-Rich Domain Data Development Drug Targeting Environment Epilepsy Family Fluorescence Resonance Energy Transfer Fragile X Syndrome Functional disorder Funding G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors Glioma Glutamates Goals Grant Heterodimerization Human In Vitro Knowledge Learning Ligand Binding Ligands Lipids Malignant Neoplasms Mediating Membrane Membrane Proteins Metabotropic Glutamate Receptors Methodology Methods Microscopy Modeling Molecular Molecular Conformation Motion Mutagenesis Nature Parkinson Disease Pattern Pharmaceutical Preparations Physiological Process Property Protein Conformation Protein Dynamics Protein Engineering Protomer Psychotic Mood Disorders Receptor Activation Receptor Signaling Reporter Research Resolution Role Schizophrenia Sensory Shapes Signal Pathway Signal Transduction Signaling Molecule Site Spectrum Analysis Structure Techniques Time Tissues Transmembrane Domain Venus Flytrap Work addiction autism spectrum disorder base crosslink design dimer drug development glutamatergic signaling human disease insight intercellular communication live cell imaging member metabotropic glutamate receptor 2 millisecond multidisciplinary nanometer nervous system disorder neuroregulation new technology novel rational design receptor receptor function reconstitution side effect single molecule single-molecule FRET spectroscopic survey therapeutically effective

项目摘要

Project Summary G protein-coupled receptors (GPCRs) are the largest family of membrane receptors in human and have emerged as the largest family of drug targets with more than 35% of all drugs on the market functioning through GPCRs. Despite their desirability, to date, many GPCR families remain undrugged, partly due to lack of mechanistic knowledge about their activation and modulation. Metabotropic glutamate receptors (mGluRs) are members of class C GPCRs and are critical modulators of glutamate signaling. Due to their widespread expression in tissue and their central role they are among the most promising drug targets for the neurological disorders such as fragile X syndrome, epilepsy, anxiety, schizophrenia as well as some cancers. Advances in protein engineering and functional, structural and computational methods in the past twenty years have provided insights into the architecture, signaling and expression patterns of mGluRs. However, a general model of how ligands change the shape of mGluRs and how this conformational change is relayed across the membrane and over 12 nm to activate specific signaling pathways is poorly understood. In this research we will develop a novel technology that will allow us to watch a single mGluR protein while functioning in physiological conditions, in real time. This will allow us to quantify the motions of different domains of the receptor that are involved in signaling. Next, we will employ this approach to study how synthetic modulators of mGluR signaling affect protein conformation and dynamics to cholesterol and affect receptor signaling. This is a multi-disciplinary proposal where state-of-the-art in vitro single-molecule FRET (smFRET) spectroscopy is complemented by live-cell imaging, protein engineering and biophysical and biochemical methods. Once accomplished, the proposed research could provide a critical step towards rational design of efficient drugs with fewer undesirable side effects. Furthermore, these studies will provide a general roadmap for quantitative high-resolution structure-function studies of mammalian membrane proteins.

项目总结