Gating Mechanism of NMDA Receptors

NMDA 受体的门控机制

基本信息

批准号：
10413208
负责人：
Gabriela K Popescu
金额：
$ 34.79万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-15 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10413208
关键词：
Address Adult Agonist Alzheimer&apos s Disease Architecture Characteristics Computer Simulation Coupled Cryoelectron Microscopy Custom Data Development Diagnosis Disease Electrophysiology (science)Epilepsy Family Functional disorder Glutamate Receptor Goals Grain Hot Spot Huntington Disease Image Intervention Kinetics Knowledge Length Link Maps Measurement Missense Mutation Modeling Molecular Conformation Movement Mutation N-Methyl-D-Aspartate Receptors Nerve Degeneration Neuraxis Neurologic Neurotransmitter Receptor Output Parkinson Disease Pathologic Pathology Patients Pharmacology Play Property Protein Isoforms Reaction Receptor Gene Records Rest Roentgen Rays Role Schizophrenia Series Shapes Site Specificity Stroke Structural Models Structure Synapses Synaptic Transmission Synaptic plasticity Testing Thermodynamics addiction antagonist base chronic pain clinically relevant computerized tools desensitization disease-causing mutation kinetic model member molecular dynamics molecular modeling mutant neurophysiology neuropsychiatric disorder prevent protein structure receptor

项目摘要

Abstract NMDA receptors play critical roles during the normal development and function of central synapses. Mutant receptors were recently identified in patients with neurologic and psychiatric conditions and were found to be causal to the diagnosed dysfunctions. The long-term objective of this project is to correlate functional receptor states postulated by the established kinetic mechanism with structural conformations. Specifically, the two aims proposed here will integrate molecular dynamics simulations and electrophysiological measurements to delineate plausible conformations for the adult NMDA receptor isoform in closed and open conformations and for a series of rationally-targeted and naturally occurring, pathologic NMDA receptor mutants. Results will elucidate the NMDA receptor gating reaction and the mechanism by which single-residue substitutions change structure and cause dysfunction.

抽象的 NMDA受体在中央突触的正常发展和功能中起关键作用。突变体最近在神经系统和精神病患者中鉴定了受体，发现受体是诊断功能障碍的因果。该项目的长期目标是将功能受体相关联由已建立的动力学机制带有结构构象的状态。具体而言，这两个目标这里提出的将将分子动力学模拟和电生理测量集成到在封闭式和开放构象中描述成年NMDA受体同工型的合理构象，对于一系列具有理性靶向且自然存在的病理性NMDA受体突变体。结果将阐明NMDA受体门控反应和单一占用变化的机制结构并引起功能障碍。