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: 7492908
• 负责人: Michaela Jansen
• 金额: $ 9万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 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 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7492908
• 关键词: Acetylcholine; Agonist; Alzheimer' s Disease; Aminobutyric Acid; Aminobutyric Acids; Attention deficit hyperactivity disorder; Autonomic nervous system; Binding; Binding Proteins; Binding Sites; Bioinformatics; Brain; Cell Communication; Cells; Characteristics; Chemical Synapse; Chemicals; Cholinergic Receptors; Chromosome Pairing; Coupling; Cryoelectron Microscopy; Data; Disease; Drug usage; Event; Extracellular Domain; Faculty; Family; Family member; Funding; Gated Ion Channel; Glycine; Goals; HTR3A gene; Homologous Protein; Homology Modeling; Individual; Ion Channel; Ions; Knowledge; Learning; Ligand Binding; Ligands; Light; Lymnaea AChBP protein; Maps; Mediating; Membrane; Membrane Proteins; Mental Depression; Modeling; Molecular; Molecular Conformation; Molecular Target; Motion; Movement; Muscle; Myasthenia Gravis; Nerve; Nervous system structure; Neuromuscular Junction; Neurosciences; Neurotransmitter Receptor; Neurotransmitters; Nicotine Dependence; Nicotinic Receptors; Parkinson Disease; Pharmaceutical Preparations; Pharmacology; Physiology; Play; Pliability; Positioning Attribute; Postdoctoral Fellow; Process; Property; Protein Biochemistry; Proteins; Publications; Research; Research Personnel; Research Project Grants; Resolution; Rest; Roentgen Rays; Role; Schizophrenia; Serotonin; Signal Transduction; Specificity; Structure; Synapses; Synaptic Cleft; Synaptic Transmission; Techniques; Testing; Torpedo; Transmembrane Domain; Transmembrane Transport; base; career; design; disease-causing mutation; improved; innovation; insight; member; molecular modeling; nervous system disorder; patch clamp; presynaptic; programs; protein structure; protein structure function; receptor; receptor function; research study; three dimensional structure; tool; voltage

DESCRIPTION (provided by applicant): Dr. Michaela Jansen is a postdoctoral fellow in the lab of Dr. Myles Akabas. Her long term career goals are to obtain an independent faculty position performing research in the field of molecular physiology and pharmacology of ion channels and transporters. Her immediate career goals are to develop an independent research program that will form the basis for beginning an independent scientific career. To accomplish this she will obtain independent funding and increase her fundamental knowledge of ion channels and membrane transport and related issues of protein structure-function, bioinformatics and molecular modeling. To increase her repertoire of experimental techniques she will learn to perform patch clamp recording and single channel analysis, molecular modeling and membrane protein biochemistry. This will be accomplished in the context of a research project to study the muscle nicotinic acetylcholine receptor (AChR) 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 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 elucidate dynamic events such as thermal and gating-induced movements. AChR have been implicated in a variety of neurological diseases such as Alzheimer's and Parkinson's disease, Attention deficit hyperactivity disorder, depression, schizophrenia, myasthenia gravis and in nicotine dependence. Understanding the molecular basis of AChR function is a prerequisite for finding improved treatments for these disorders. Our results will provide valuable tools for understanding how disease causing mutations interfere with function, how drugs used clinically modulate function, and also a basis to design new drugs.

描述（由申请人提供）： Michaela Jansen 博士是 Myles Akabas 博士实验室的博士后研究员。她的长期职业目标是获得独立的教职职位，在离子通道和转运蛋白的分子生理学和药理学领域进行研究。她的近期职业目标是开发一个独立的研究项目，为开始独立的科学生涯奠定基础。为了实现这一目标，她将获得独立的资助，并增加她在离子通道和膜运输以及蛋白质结构功能、生物信息学和分子建模相关问题方面的基础知识。为了增加她的实验技术，她将学习进行膜片钳记录和单通道分析、分子建模和膜蛋白生物化学。这将在一个研究项目的背景下完成，该项目旨在研究肌肉烟碱乙酰胆碱受体（AChR）结构及其在通道激活过程中经历的构象变化。烟碱乙酰胆碱受体介导神经肌肉连接处和大脑中的快速突触传递。最近发表的ACh结合蛋白（AChBP）和Torpedo AChR结构使人们对三维结构有了新的认识，为以下具体目标提供了基础：1）通过以下方法测试4-A分辨率AChR跨膜结构域模型的有效性确定特定跨膜片段残基之间的邻近关系。 2) 确定 M2 通道衬里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。 4) 探测 M2-M3 环周围的蛋白质堆积，该环参与配体结合到通道门控的转导。结果将验证从 4-A 分辨率数据推断出的结构信息。此外，他们还将阐明动态事件，例如热和门控引起的运动。 AChR 与多种神经系统疾病有关，如阿尔茨海默病和帕金森病、注意力缺陷多动障碍、抑郁症、精神分裂症、重症肌无力和尼古丁依赖。了解 AChR 功能的分子基础是寻找改善这些疾病治疗方法的先决条件。我们的结果将为了解导致疾病的突变如何干扰功能、临床使用的药物如何调节功能以及设计新药物的基础提供有价值的工具。

项目成果

Engineering a prokaryotic Cys-loop receptor with a third functional domain.

设计具有第三个功能域的原核半胱环受体。

• 发表时间: 2011-10-07
• 作者: Goyal, Raman;Salahudeen, Ahmed Abdullah;Jansen, Michaela
• 通讯作者: Jansen, Michaela

Probing protein packing surrounding the residues in and flanking the nicotinic acetylcholine receptor M2M3 loop.

探测烟碱乙酰胆碱受体 M2M3 环中残基周围和侧翼的蛋白质堆积。

• 发表时间: 2009-02-11
• 作者: Wiltfong, Roger Ernest;Jansen, Michaela
• 通讯作者: Jansen, Michaela

Structural sensitivity of a prokaryotic pentameric ligand-gated ion channel to its membrane environment.

原核五聚体配体门控离子通道对其膜环境的结构敏感性。

• 发表时间: 2013-04-19
• 作者: Labriola, Jonathan M;Pandhare, Akash;Jansen, Michaela;Blanton, Michael P;Corringer, Pierre;Baenziger, John E
• 通讯作者: Baenziger, John E