Integration of Computational and Biological Analysis of Serotonin Transporters

血清素转运蛋白的计算和生物学分析的整合

• 批准号: 7588177
• 负责人: Loren Keith Henry
• 金额: $ 6.14万
• 依托单位: UNIVERSITY OF NORTH DAKOTA
• 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 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7588177
• 关键词: Amino Acids; Antidepressive Agents; Area; Autistic Disorder; Binding; Binding Sites; Biochemical; Biochemistry and Pharmacology Cancer Activity; Biological; Biology; Chemicals; Clinical; Cocaine; Complex; Computational Biology; Computer Simulation; Data; Development; Disease; Docking; Drosophila genus; Environment; Evolution; Experimental Models; Family; Family member; Future; Genes; Homologous Gene; Human; Individual; Integral Membrane Protein; Investigation; Ions; Laboratories; Leucine; Ligands; Link; Membrane; Membrane Proteins; Mental Depression; Mental Health; Mental disorders; Methodology; Methods; Modeling; Modification; Molecular; Movement; Mutagenesis; Mutation; Nervous system structure; Neurologic; Neurons; Obsessive-Compulsive Disorder; Pattern; Placement; Play; Principal Investigator; Process; Property; Proteins; Purpose; Research; Research Personnel; Resolution; Role; Sampling; Sequence Alignment; Serotonin; Side; Signal Transduction; Structural Models; Structure; Substrate Specificity; Synaptic Vesicles; Testing; Therapeutic; Therapeutic Agents; Today; Training; Traumatic Stress Disorders; Tryptamines; Uncertainty; United States National Institutes of Health; Universities; Validation; Variant; Vertebral column; addiction; base; clinically relevant; club drug; comparative; computer studies; dopamine transporter; drug of abuse; ecstasy; extracellular; insight; instructor; knowledge base; method development; molecular dynamics; monoamine; mutant; neuropsychiatry; neurotransmitter release; presynaptic; protein folding; serotonin transporter; small molecule; solute; symporter; tryptamine

DESCRIPTION (provided by applicant): The purpose of this project is to utilize current experimental data to construct a relevant comparative structural model of the serotonin transporter (SERT) based on a recently crystallized bacterial family member. Recent advancements in computation protein folding have legitimized its use in modeling integral membrane proteins. The principal investigator, who has obtained a strong background in the study of structural aspects of SERT using biochemistry and pharmacology in the laboratory of Dr. Randy Blakely who has an outstanding research record in this area, will pursue training in the area of computational biology with a talented researcher, Dr. Jens Meiler, who has played an intergral role in development of methods to analyze protein-small molecule interaction in silico. This project with its heavy emphasis on computational modeling represents a new direction in research for the P.I. who to date has focused on molecular/biochemical study of membrane proteins. Vanderbilt University offers a superior environment for computational studies through the NIH supported ACCRE processor cluster and multiple genes formally expressed in membrane protein modeling (Lybrand, Chazin). This training will allow Dr. Henry to build, test and refine models of SERT interactions with its substrate serotonin and the club drug MDMA. These studies have the potential to provide significant insight into the structural components necessary for recognition and movement of sertonin and drugs of abuse through the transporter. Furthermore, this training will allow Dr. Henry to apply these methods to future projects and broaden his knowledge base as an academic instructor/investigator. Relevance: The serotonin transporter is arguably the most clinically relevant protein today. It is the major target of antidepressants and several drugs of abuse and has been linked to several psychological disorders including: depression, obsessive-compulsive disorder, post-traumatic stress disorder and more recently to aspects of autism. However, we still do not understand many of the details of how SERT recognizes and moves substrates like serotonin and MDMA into the nerve cell. Understanding these aspects of such an important process in the nervous system could have an important impact on clinical targeting of SERT as well as the related norepinepherine and dopamine transporters all which play critical roles in our neurological and psychological health.

描述（由申请人提供）：本项目的目的是利用当前的实验数据构建基于最近结晶的细菌家族成员的血清素转运体（SERT）的相关比较结构模型。最近在计算蛋白质折叠方面的进展使其在模拟整体膜蛋白方面的应用合法化。首席研究员在Randy Blakely博士的实验室中利用生物化学和药理学研究SERT的结构方面获得了强大的背景，Randy Blakely博士在该领域有着杰出的研究记录，他将在计算生物学领域与一位才华横溢的研究员Jens Meiler博士一起进行培训，Jens Meiler博士在开发分析蛋白质-小分子相互作用的方法方面发挥了不可或缺的作用。该项目以计算建模为重点，代表了迄今为止专注于膜蛋白分子/生化研究的pi研究的新方向。范德比尔特大学通过NIH支持的ACCRE处理器集群和膜蛋白模型中正式表达的多个基因，为计算研究提供了优越的环境（Lybrand, Chazin）。这项培训将使Henry博士能够建立、测试和完善SERT与其底物血清素和俱乐部药物MDMA相互作用的模型。这些研究有可能为通过转运体识别和移动血清素和滥用药物所必需的结构成分提供重要的见解。此外，这次培训将使亨利博士能够将这些方法应用于未来的项目，并扩大他作为学术讲师/调查员的知识基础。相关性：血清素转运蛋白可以说是当今最具临床相关性的蛋白质。它是抗抑郁药和一些滥用药物的主要目标，并与几种心理障碍有关，包括：抑郁症、强迫症、创伤后应激障碍，以及最近的自闭症。然而，我们仍然不了解SERT如何识别和移动底物，如血清素和MDMA进入神经细胞的许多细节。了解神经系统中这一重要过程的这些方面可能对SERT的临床靶向以及相关的去甲肾上腺素和多巴胺转运体产生重要影响，这些转运体在我们的神经和心理健康中起着至关重要的作用。