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: 7992404
• 负责人: Michaela Jansen
• 金额: $ 24.04万
• 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 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7992404
• 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.

本研究旨在研究肌肉烟碱型乙酰胆碱受体(NAChR)的结构及其在通道激活过程中的构象变化。烟碱型乙酰胆碱受体在神经-肌肉接头和脑中介导快速突触传递。最近ACh结合蛋白(AChBP)和鱼雷AChR结构的发表使人们对AChR的三维结构有了新的了解，并为以下特定目标提供了基础：1)通过确定特定跨膜片段残基之间的邻近关系来测试4-A分辨率AChR跨膜域模型的有效性。2)确定M2通道衬砌节段在静止和激活状态下的热迁移率。3)绘制激活过程中跨膜结构域的结构变化图。4)探讨M2-M3环周围的蛋白质堆积，参与配体结合到通道门控的转导。结果将验证从4-A分辨率数据中推断的结构信息。此外，它们还将用于改进受体的结构模型。这将允许更详细地研究变构配体的结合部位，从而允许设计改进的药物，此外，这项研究将阐明动态事件，如热和门控诱导的运动。