DISTINCTIVE RECEPTOR ACTIONS IN HALLUCINOGEN MECHANISMS

致幻剂机制中独特的受体作用

• 批准号: 7298950
• 负责人: HAREL WEINSTEIN
• 金额: $ 28.68万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7298950
• 关键词: Address; Affect; Agonist; Animal Behavior; Arrestin; Arrestins; Arts; Attention; Be++ element; Behavioral; Beryllium; Binding; Bioinformatics; Biological Models; Biophysics; C-terminal; Cell physiology; Cells; Characteristics; Class; Classification; Collaborations; Communities; Complex; Computational Biology; Computer Simulation; Computing Methodologies; DLG4 gene; DNA Sequence Rearrangement; Data; Databases; Development; Dimerization; Disruption; Dissociation; Elements; Engineering; Environment; Ergoline; Ergolines; Evaluation; Experimental Designs; Fingerprint; G-Protein-Coupled Receptors; GTP-Binding Proteins; Gene Expression Profile; Goals; Hallucinogens; Homo; In Vitro; Indium; Information Management; Investigation; Knock-in Mouse; Lead; Learning; Letters; Libraries; Ligand Binding; Ligands; Literature; Management Information Systems; Maps; Measurement; Measures; Membrane Proteins; Mescaline; Methods; Modeling; Molecular; Mutate; Mutation; N,N-Dimethyltryptamine; Nature; Neurotransmitters; Numbers; Outcome; Pathway interactions; Pattern; Peptides; Phenethylamines; Phospholipids; Phosphoproteins; Phosphorylation; Principal Investigator; Process; Property; Protein Dynamics; Protein Engineering; Proteins; Protocols documentation; Publishing; Range; Receptor Signaling; Recycling; Regulation; Research; Research Personnel; Role; Scaffolding Protein; Serotonin; Serotonin Receptor 5-HT2A; Signal Pathway; Signal Transduction; Simulate; Site; Solvents; Sorting - Cell Movement; Specificity; Structural Models; Structure; Study models; System; Testing; Therapeutic; Validation; Water; Work; base; computer studies; computerized data processing; design; dimer; discrete data; drug of abuse; insight; mathematical model; membrane model; models and simulation; molecular modeling; monomer; mutant; neurophysiology; novel; programs; protein protein interaction; receptor; receptor function; research study; response; scaffold; serotonin receptor; simulation; stem; three dimensional structure; tool; trafficking

This component of the PPG is dedicated to quantitative, structural, and computational modeling aspects of our collaborative effort to understand the mechanisms of hallucinogenic drugs in various tructural classes, triggered by their interactions with the subtypes of 5-HT GPCRs. The aim to understand the mechanisms that engender the complex behavioral effects in hallucinogenesis, is based on the hypothesis that the hallucinogenic potential of certain compounds results from specific modes of interaction with these receptors, that produce distinct molecular signaling mechanisms; thus, hallucinogens trigger structural and dynamic receptor responses (affecting protein-protein interactions) that differ from those produced by other ligands. This hypothesis leads to proposed investigations of (i) the modes of receptor response (conformational rearrangements and stabilization of "activated state(s)") that trigger special protein-protein interactions ranging from receptor oligomerization to interactions with various scaffolding proteins (e.g., PDZ- BAR-domains), and (ii) how such conformational rearrangements and resulting association/dissociation of protein- protein interactions affect selectivity and efficiency in the signaling pathways of hallucinogens. We develop and apply computational methods, modeling and simulation approaches (from structural biophysics, bioinformatics, predictive mathematical modeling) to study molecular and cellular signaling systems involved in the mechanisms. The studies are closely coordinated with Projects 2 and 3 of the PPG in which probing and validation of the models will be based on collaboratively designed experiments utilizing inferences, designs and protein constructs investigated in this project. These collaborative studies will serve to incorporate the structural context of molecular interactions in systems level models of the hallucinogen signaling mechanisms. The components of a hallucinogen signaling map will be stored in an information management system (SigPath) ultimately used to model quantitatively the pathways and learn about their characteristic properties, and their integration in the cellular machinery. We plan to start with modest, scientifically responsible simulations of small pathway elements in order to support hypothesis testing and design of experiments in the PPG that explore such pathways.

PPG的这一组成部分致力于定量、结构和计算建模 我们合作努力的各个方面，以了解致幻药物在不同领域的作用机制 结构类，由它们与5-羟色胺GPCRs亚型的相互作用触发。目的是为了 了解在幻觉发生中产生复杂行为影响的机制，是 基于这样的假设，即某些化合物的致幻潜力是由特定的 与这些受体相互作用的方式，产生不同的分子信号机制； 因此，迷幻剂触发结构和动态受体反应(影响蛋白质-蛋白质 相互作用)，不同于其他配体产生的那些。这一假设导致了提出 研究(I)受体反应的方式(构象重排和 激活状态(S)的稳定化)引发特殊的蛋白质-蛋白质相互作用 受体寡聚与各种支架蛋白的相互作用(例如，PDZ-bar结构域)， 以及(Ii)蛋白质的这种构象重排和由此产生的结合/解离- 蛋白质相互作用影响致幻剂信号通路的选择性和效率。我们 开发和应用计算方法、建模和模拟方法(来自结构 生物物理学、生物信息学、预测数学建模)来研究分子和细胞 参与该机制的信号系统。这些研究与项目2密切协调。 和3个PPG，其中模型的探测和验证将基于协作 利用推论、设计和所研究的蛋白质结构的设计性实验 项目。这些合作研究将有助于纳入分子的结构背景 迷幻剂信号机制的系统水平模型中的相互作用。的组件 迷幻剂信号图将存储在信息管理系统(SigPath)中 最终用于对路径进行定量建模并了解其特征属性， 以及它们在蜂窝机械中的整合。我们计划从谦虚、科学的角度出发 负责任的小途径元素模拟，以支持假设检验和 在PPG中设计探索这种途径的实验。