Nicotinic Acetylcholine Receptor Structure, Thermal Motion and Gating

烟碱乙酰胆碱受体结构、热运动和门控

• 批准号: 7743395
• 负责人: Michaela Jansen
• 金额: $ 24.65万
• 依托单位: TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-15 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7743395
• 关键词: Alzheimer' s Disease; Attention deficit hyperactivity disorder; Binding Proteins; Binding Sites; Brain; Cholinergic Receptors; Data; Disease; Drug usage; Event; Extracellular Domain; Investigation; Ligand Binding; Ligands; Maps; Mediating; Mental Depression; Modeling; Molecular; Motion; Movement; Muscle; Myasthenia Gravis; Nerve; Nicotine Dependence; Nicotinic Receptors; Parkinson Disease; Pharmaceutical Preparations; Proteins; Publications; Research Project Grants; Resolution; Rest; Schizophrenia; Structural Models; Structure; Synaptic Transmission; Testing; Torpedo; Transmembrane Domain; base; design; flexibility; improved; insight; receptor; three dimensional structure

This research project aims at studying the muscle nicotinic acetylcholine receptor (nAChR) structure and the conformational changes it undergoes during channel activation. Nicotinic AChR mediate fast synaptic transmission at the nerve-muscle junction and in the brain. The recent publication of the ACh binding protein (AChBP) and Torpedo AChR structures has allowed new insights into the three dimensional structure and provides the basis for the following Specific Aims: 1) To test the validity of the 4-A resolution AChR transmembrane domain model by determining proximity relationships between specific transmembrane segment residues. 2) To determine the thermal mobility of the M2 channel-lining segments in the resting and activated states. 3) To map structural changes in the transmembrane domain during activation. 4) To probe protein packing around the M2-M3 loop that is involved in the transduction of ligand binding to channel gating. The results will validate the structural information inferred from the 4-A resolution data. In addition they will be used to refine the structural model of the receptor. This will allow more detailed investigations of binding sites for allosteric ligands, thus allowing design of Improved drugs, in addition, this study will elucidate dynamic events such as thermal and gating-induced movements.

该研究项目旨在研究肌肉烟碱乙酰胆碱受体（NACHR）结构，并在通道激活期间经历的构象变化。烟碱ACHR介导神经肌肉结和大脑处的快速突触传播。最新的ACH结合蛋白（ACHBP）和Torpedo ACHR结构的发表允许对三维结构进行新的见解，并为以下特定目的提供了基础：1）通过确定特定的跨膜群之间的特定跨膜段残留物之间的邻近性关系，以测试4-A分辨率ACHR跨膜结构域模型的有效性。 2）确定在静息状态和激活状态下M2通道段段的热迁移率。 3）在激活过程中绘制跨膜结构域中的结构变化。 4）探测蛋白质围绕M2-M3环的填料，该环与配体结合与通道门控的转导有关。结果将验证从4-A分辨率数据推断出的结构信息。另外，它们将用于完善受体的结构模型。这将允许对变构配体的结合位点进行更详细的研究，从而允许设计改进的药物，此外，这项研究将阐明动态事件，例如热和门控诱导的运动。