Structural basis of nicotinic acetylcholine receptor gating and toxin inhibition

烟碱乙酰胆碱受体门控和毒素抑制的结构基础

基本信息

批准号：
10848770
负责人：
Ryan E Hibbs
金额：
$ 69.83万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
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：
2022-01-01 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10848770
关键词：
Agonist Amino Acids Anesthetics Architecture Autoantibodies Binding Biophysics Brain Cell Surface Receptors Central Nervous System Chemosensitization Complement Complex Cone Cryoelectron Microscopy Data Drug Targeting Electric Organ Electrophysiology (science)Equilibrium Exposure to Freezing Goals Human Inflammation Ion Channel Gating Ions Ligands Lipids Measurement Mediating Mental disorders Modeling Molecular Chaperones Molecular Conformation Muscle Muscle Contraction Muscle Weakness Mutagenesis Mutation Myasthenic Syndrome N-Methyl-D-Aspartate Receptors Nerve Degeneration Neurodegenerative Disorders Neuromuscular Blocking Agents Neurons Neurotransmitter Receptor Neurotransmitters Nicotinic Receptors Peptides Peripheral Nervous System Permeability Pharmacology Physiological Preparation Property Receptor Activation Receptor Inhibition Research Resolution Route Side Snail Venoms Snakes Structure Therapeutic Time Torpedo Toxin Venoms addiction alpha Bungarotoxin alpha-Conotoxin cell type computer studies conformational conversion density desensitization design experimental study improved lens member millisecond molecular dynamics nanodisk nervous system disorder neurotransmission particle positive allosteric modulator receptor reconstitution restraint simulation small molecule therapeutic target

项目摘要

Nicotinic acetylcholine receptors are therapeutic targets for neurodegenerative disorders, addiction, and mental illness. These pentameric ligand-gated ion channels are prototypical members of the Cys-loop receptor superfamily, which mediate fast neurotransmission throughout the central and peripheral nervous systems. Fundamental questions about nicotinic receptor biophysics and pharmacology remain, due in large part to the limited high-resolution structural information. We propose to determine high-resolution structures of two archetypal nicotinic receptor subtypes using single particle cryo-electron microscopy and investigate structure- based mechanistic hypotheses using molecular dynamics simulations and electrophysiology. Our first target is the muscle-type nicotinic receptor, the founding member of the pentameric receptor superfamily. Mutations in the channel, as well as autoimmune antibodies to the receptor, cause myasthenic syndromes. Our second target is the human α7 nicotinic receptor. α7 is exceptional among nicotinic receptors in several ways: it assembles physiologically as a homopentamer, it is expressed abundantly in the brain but also in non- electrically excitable cell types, it has a high permeability to Ca2+, and it desensitizes in microseconds. The receptor is a target in neurodegenerative disease, addiction and inflammation. We propose to use single particle cryo-electron microscopy combined with mutagenesis, electrophysiology and molecular dynamics simulations to elucidate mechanisms of channel activation, ligand recognition and ion permeation in these two distinctinctive nicotinic receptor subtypes to define general mechanisms and idiosyncratic properties.

烟碱乙酰胆碱受体是神经退行性疾病，成瘾和精神的热靶标疾病。这些五聚合配方门控离子通道是Cys-loop接收器的典型成员超家族介导整个中央和周围神经系统中的快速神经传递。关于烟碱受体生物物理学和药理学的基本问题仍然很大程度上归因于有限的高分辨率结构信息。我们建议确定两个的高分辨率结构使用单粒子冷冻电子显微镜的原型烟碱受体亚型，并研究结构使用分子动力学模拟和电生理学的基于机械假设。我们的第一个目标是肌肉型烟碱受体，五聚体受体超家族的创始成员。突变通道以及对接收器的自身免疫性抗体，引起肌无力综合征。我们的第二个靶标是人α7烟碱受体。 α7在几种方面是烟碱受体中的例外：它在物理上以同型聚体的形式组装，它在大脑中彻底表达，但在非 - 电细胞类型，它对Ca2+具有很高的渗透性，并且在微秒中脱敏。这受体是神经退行性疾病，成瘾和炎症的靶标。我们建议使用单个粒子冷冻电子显微镜结合诱变，电生理学和分子动力学结合阐明这两种通道激活，配体识别和离子渗透机制的模拟独特的烟碱受体亚型，以定义一般机制和特质性质。