Agonist induced conformational changes in the NMDA receptor

激动剂诱导 NMDA 受体构象变化

• 批准号: 10001582
• 负责人: Ryan James Durham
• 金额: $ 3.25万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10001582
• 关键词: Affect; Agonist; Alzheimer' s Disease; Architecture; Basic Science; Binding; Binding Sites; Biological Process; Communication; Data; Dissociation; Electrophysiology (science); Epilepsy; Exhibits; Fluorescence Resonance Energy Transfer; Foundations; Glutamates; Glycine; Human; Huntington Disease; Image; Investigation; Ion Channel Gating; Ischemic Stroke; Knowledge; Learning; Length; Ligands; Lobe; Mediating; Mediator of activation protein; Memory; Methods; Mission; Molecular Conformation; Mutation; N-Methyl-D-Aspartate Receptors; NMDA receptor A1; National Institute of General Medical Sciences; Neuraxis; Neurodegenerative Disorders; Parkinson Disease; Pathologic; Physiological; Play; Prevention; Process; Proteins; Regulation; Research; Resolution; Roentgen Rays; Role; Structure; Synaptic plasticity; Testing; Transmembrane Domain; Work; crosslink; dimer; disease diagnosis; excitotoxicity; experimental study; insight; nervous system disorder; neurotransmission; receptor; receptor function; receptor structure function; single molecule; single-molecule FRET

Abstract: NMDA receptors are ligand-gated ion channels that play a critical role in the function of the central nervous system and are involved in processes such as synaptic plasticity, learning, and memory. In addition to their physiological functions, NMDARs are also implicated in a number of neurological diseases and conditions, including ischemic stroke and epilepsy. The diverse roles that NMDA receptors fill make it critical that the function and regulation of these receptors are fully understood. The recent structures have provided insight into the architecture and end state structures of NMDA receptors providing a rich foundation for structure- dynamic investigation of the receptor which will allow for detailed investigations of all the conformational states that the protein explores. This is required as there are still several unanswered questions such as mechanism underlying partial agonism as well as mechanism of allosteric communication between the glutamate and glycine binding. Single molecule Förster Resonance Energy Transfer (smFRET) method is ideally suited for such investigations as it allows for the characterization of all the states that the proteins probes and dynamics of transitions between the states, which then can be correlated to the extensive functional information available for the receptor. The research proposed herein seeks to fill these important gaps in knowledge through two aims: to Determine the mechanism of partial agonism in the NMDA receptor and to Study the allosteric communication between the glutamate- and glycine-binding subunits of the NMDA receptor. The research proposed will provide a significant step forward in the understanding of the function and regulation of the NMDA receptor. This research pursuit, therefore, is in keeping with the stated mission of the NIGMS to support “basic research that increases understanding of biological processes and lays the foundation for advances in disease diagnosis, treatment and prevention”.

抽象的： NMDA受体是配体门控离子通道，在中枢神经的功能中起关键作用 系统并参与诸如合成可塑性，学习和记忆等过程。除了他们 生理功能，NMDAR也在许多神经系统疾病和疾病中实施， 包括缺血性中风和癫痫。 NMDA接收器填补的潜水员角色使得 这些受体的功能和调节已充分理解。最近的结构提供了有关 NMDA接收器的结构和最终状态结构为结构动态提供了丰富的基础 对接收器的调查将允许对所有构象的详细研究表明 蛋白质探索。这是必需的，因为仍然有几个未解决的问题，例如机制 谷氨酸和谷氨酸和 甘氨酸结合。单分子förster共振能传递（SMFRET）方法非常适合 这样的投资允许表征蛋白质问题和动态的所有州的表征 州之间的过渡，然后可以将其与可用的广泛功能信息相关联 对于接收器。本文提出的研究旨在通过两个 目的：确定NMDA接收器中部分档案的机制并研究变构 NMDA接收器的谷氨酸和甘氨酸结合亚基之间的通信。研究 拟议的将在理解功能和调节方面迈出重要 NMDA接收器。因此，这项研究的追求与诺格姆斯的既定任务保持一致 “基础研究提高对生物过程的了解并为进步的基础奠定了基础 疾病诊断，治疗和预防。