Integration of Computational and Biological Analysis of Serotonin Transporters

描述(申请人提供)：本项目的目的是利用当前的实验数据，基于一个最近结晶的细菌家族成员，构建一个相关的5-羟色胺转运体(SERT)的比较结构模型。最近在计算蛋白质折叠方面的进展已经使其在整体膜蛋白质建模中的使用合法化。首席研究人员在兰迪·布莱克利博士的实验室利用生物化学和药理学研究SERT的结构方面具有很强的背景，他在这一领域有着杰出的研究记录，他将与才华横溢的研究员延斯·迈勒博士一起进行计算生物学领域的培训，延斯·迈勒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整体作用。这项侧重于计算模拟的项目代表了P.I.的一个新的研究方向，他们到目前为止一直专注于膜蛋白的分子/生化研究。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(Lybrand，Chazin)中正式表达的多个基因，为计算研究提供了一个优越的环境。这项培训将使亨利博士能够建立、测试和改进SERT与其底物5-羟色胺和俱乐部药物MDMA相互作用的模型。这些研究有可能为识别和转运血清素和滥用药物通过转运体所需的结构成分提供重要的见解。此外，这项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：5-羟色胺转运体可以说是当今临床上最相关的蛋白质。它是抗抑郁药物和几种滥用药物的主要靶点，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如何识别和移动像5-羟色胺和MDMA这样的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对于SERT的临床靶向以及相关的去甲肾上腺素和多巴胺转运体都有重要的影响，这些都在我们的神经和心理健康中发挥着关键作用。

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.