Integration of Computational and Biological Analysis of Serotonin Transporters

描述（由申请人提供）：本项目的目的是利用当前的实验数据，基于最近结晶的细菌家族成员构建5-羟色胺转运蛋白（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建模完整膜蛋白中的使用合法化。主要研究者在Randy Blakely博士的实验室中使用生物化学和药理学研究SERT的结构方面获得了很强的背景，他在这一领域有着出色的研究记录，他将与一位才华横溢的研究人员Jens Meiler博士一起在计算生物学领域进行培训，他在开发计算机分析蛋白质-小分子相互作用的方法方面发挥了重要作用。该项目以其对计算建模的高度重视代表了P.I.研究的新方向。迄今为止，世卫组织一直专注于膜蛋白的分子/生物化学研究。范德比尔特大学通过NIH支持的ACCRE处理器集群和在膜蛋白建模中正式表达的多个基因为计算研究提供了上级环境（Lybrand，Chazin）。这项培训将使亨利博士能够建立，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。这些研究有可能提供显着的洞察力的识别和运动的血清素和药物滥用通过转运蛋白所必需的结构组成部分。此外，该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/研究人员的知识基础。相关性：血清素转运蛋白可以说是当今临床上最相关的蛋白质。它是抗抑郁药和几种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，最近还与自闭症有关。然而，我们仍然不了解SERT如何识别和移动血清素和MDMA等底物进入神经细胞的许多细节。了解神经系统中如此重要的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蛋白产生重要影响，所有这些都在我们的神经和心理健康中发挥关键作用。

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.