alpha7 nicotinic acetylcholine receptor allosteric modulation and native structure

α7烟碱乙酰胆碱受体变构调节和天然结构

• 批准号: 10678472
• 负责人: Sean Michael Burke
• 金额: $ 3.39万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10678472
• 关键词: Affinity; Affinity Chromatography; Alzheimer' s Disease; Animal Model; Anxiety Disorders; Binding; Binding Sites; Biology; Cells; Characteristics; Chemical Structure; Chemosensitization; Classification; Clinical Trials; Complement; Complex; Cryoelectron Microscopy; Data; Development; Disease; Doctor of Philosophy; Drug Binding Site; Drug Design; Effectiveness; Exhibits; Family; Foundations; Future; Goals; Homo; Impaired cognition; Inflammation; Ion Channel Gating; Left; Ligands; Link; Mediating; Methods; Molecular Conformation; Molecular Structure; Muscle; Nervous System; Neurodegenerative Disorders; Neurons; Neurotransmitters; Nicotinic Receptors; Parkinson Disease; Permeability; Pharmacology; Play; Property; Proteins; Recombinants; Research; Resolution; Role; Schizophrenia; Signal Transduction; Source; Structure; Testing; Therapeutic; Therapeutic Intervention; Tissues; Training; Work; addiction; alpha-bungarotoxin receptor; brain tissue; desensitization; drug development; experience; experimental study; holistic approach; human disease; improved; in vivo; neurotransmission; particle; positive allosteric modulator; pre-clinical; preservation; receptor; stoichiometry; success; therapeutic target

Project Summary/Abstract: Nicotinic acetylcholine receptors are pentameric ligand-gated ion channels responsible for excitatory signaling throughout the nervous system. The α7 nicotinic receptor subtype is a widely expressed subtype that is unique among nicotinic receptors in that it forms a functional homopentamer, desensitizes rapidly, and is exceptionally permeable to Ca2+. It plays a prominent role in human disease with dysregulation of α7 linked to Alzheimer’s disease, schizophrenia, and inflammation. α7’s unique characteristics and involvement in disease have made it an attractive therapeutic target leading to the development of numerous compounds aimed at enhancing α7 activity. Among the most promising strategies are positive allosteric modulators (PAMs). PAMs increase receptor activity while maintaining the spatial and temporal characteristics of endogenous neurotransmission. Despite strong functional characterization, precise modulator binding sites and structural mechanisms of potentiation remain unknown, representing a major roadblock towards rational drug design. Moreover, while α7 can uniquely assemble as a functional homopentamer, it can also associate with other subtypes forming a heteromer, yielding increased diversity and altered channel properties. The degree of α7 channel diversity in native tissue is unclear. Thus, the major goal of this application is to resolve key questions related to the α7 subtype by elucidating receptor modulation mechanisms and determining the molecular structure of native α7. Building on previous work defining major gating cycle conformations, I aim to determine high resolution structures of α7 complexed with numerous allosteric modulators. In parallel, I will develop a method to purify native α7 from brain tissue and determine the structure of α7-containing channels using single particle cryo-EM. Taken together, this work will define mechanisms of receptor modulation and native α7 structure and subunit stoichiometry, enhancing our understanding of α7 biology and pharmacology. Furthermore, this work will provide a foundation for future native receptor purification and aid drug development towards the entire nicotinic receptor family.

项目摘要/摘要： 烟碱乙酰胆碱受体是五聚体配体门控离子通道，负责兴奋性 α7 烟碱受体亚型是一种广泛表达的亚型。 在烟碱受体中是独特的，因为它形成功能性同五聚体，快速脱敏，并且 它对 Ca2+ 具有特殊的渗透性，在与 α7 失调相关的人类疾病中发挥着重要作用。 阿尔茨海默病、精神分裂症和炎症。α7 的独特特征及其与疾病的关系。 使其成为一个有吸引力的治疗靶点，从而导致了许多针对以下疾病的化合物的开发： 增强 α7 活性是最有前途的策略之一。 增加受体活性，同时保持内源性的空间和时间特征 尽管具有强大的功能特征、精确的调节剂结合位点和结构。 增强机制仍然未知，这是合理药物设计的主要障碍。 此外，虽然α7可以独特地组装为功能性同五聚体，但它也可以与其他 亚型形成异聚体，从而增加多样性并改变 α7 的通道特性。 天然组织中的通道多样性尚不清楚，因此，该应用的主要目标是解决关键问题。 通过阐明受体调节机制并确定分子水平与α7亚型相关 基于之前定义主要门控循环构象的工作，我的目标是确定天然 α7 的结构。 同时，我将开发一种与多种变构调节剂复合的 α7 的高分辨率结构。 从脑组织中纯化天然α7并使用单一方法确定含α7通道的结构的方法 总而言之，这项工作将定义受体调节和天然 α7 的机制。 结构和亚基化学计量，增强我们对 α7 生物学和药理学的理解。 这项工作将为未来天然受体纯化和辅助药物开发奠定基础 整个烟碱受体家族。