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Cryo-EM Studies of the Structure and Allosteric Mechanisms of Heteromeric Glycine Receptor

异聚甘氨酸受体结构和变构机制的冷冻电镜研究

基本信息

批准号：
10388533
负责人：
Eric D. Gibbs
金额：
$ 6.98万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-01 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10388533
关键词：
Address Affect Agonist Alcohol abuse Alcohols Anesthetics Antiparasitic Agents Binding Binding Proteins Binding Sites Brain Brain Stem Cannabinoids Complex Coupling Cryoelectron Microscopy Data Disease Electron Microscopy Electron Spin Resonance Spectroscopy Electrophysiology (science)Environment Glycine Glycine Receptor Binding Glycine Receptors Goals Health Homo Ion Channel Gating Ions Ivermectin Kinetics Knowledge Ligand Binding Ligands Lipid Binding Maps Mediating Mediator of activation protein Membrane Proteins Microscope Molecular Conformation Movement Muscle Mutation Neural Inhibition Neurotransmitter Receptor Neurotransmitters Outcome Study Pain Pathology Perception Physiologic pulse Physiological Physiological Processes Preparation Process Protein Biochemistry Proteins Protocols documentation Receptor Signaling Regulation Resolution Resources Review Literature Rewards Role Sampling Sequence Analysis Site Spinal Cord Stimulus Structure Synapses Techniques Tetrahydrocannabinol Therapeutic Tinnitus Titan Training Transmembrane Domain Universities Visual Visual Perception antagonist chronic pain cryogenics design experience experimental study extracellular gephyrin insight member particle receptor binding receptor function spasticity therapeutic target

项目摘要

Project Summary and Abstract: Glycine receptors (GlyR) are the primary mediators of synaptic neural inhibition in the brainstem and spinal cord. They are essential to many physiological processes and intriguing, yet untapped, therapeutic targets. The overall goal of this project is to understand the processes that control GlyR activity and provide a template for therapeutic design. GlyR is a pentameric ligand-gated ion channel expressed in homomeric and heteromeric forms. Heteromeric GlyR is essential for synaptic activity as it alone can bind the synaptic anchoring protein gephryin. This proposal uses cryogenic electron microscopy (cryo-EM), electrophysiology and electron paramagnetic resonance (EPR) to achieve mechanistic understanding of heteromeric GlyR bound to gephryin. This will build upon past cryo-EM studies of homomeric GlyR. The specific aims of this proposal are: First, to characterize subunit-specific structures in hetero-GlyR known to regulate subunit composition, ion conduction and intracellular regulation. Second, study conformational coupling between the neurotransmitter binding pocket and channel gate. Third, explore the allosteric effects of ligands that bind within the transmembrane domain of hetero-GlyR. The applicant has shown significant progress by expressing and purifying heteromeric GlyR and performing preliminary cryo-EM studies resulting in a 2.25-2.5 Å cryo-EM map. In accomplishing this project, the applicant will receive training in membrane protein biochemistry, cryo-EM, electrophysiology and EPR. This project will take place in Sudha Chakrapani’s lab at Case Western Reserve University. This lab has made significant recent contributions to the field with cryo-EM studies of homomeric GlyR and other ligand-gated ion channels. Available resources include a cryo-EM facility with a Titan Krios microscope and lab- dedicated electrophysiology rigs. Several members of the lab have extensive experience in cryo- EM, electrophysiology and/or EPR providing an excellent training environment.

项目摘要及摘要：甘氨酸受体（Glycine receptor, GlyR）是突触的主要介质