AMINO ACID TRANSPORTER

氨基酸转运蛋白

• 批准号: 7957291
• 负责人: CHRISTOPHER CHARLES LAW
• 金额: $ 2.53万
• 依托单位: BROOKHAVEN SCIENCE ASSOC-BROOKHAVEN LAB
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7957291
• 关键词: Affinity; Amino Acid Transporter; Amino Acids; Antidepressive Agents; Binding; Binding Sites; Biological Assay; Computer Retrieval of Information on Scientific Projects Database; Crystallography; Desipramine; Drug Delivery Systems; Drug Design; Funding; Grant; Homologous Gene; Homology Modeling; Human; Institution; Light; Neurotransmitters; Pharmaceutical Preparations; Preclinical Drug Evaluation; Protein Family; Proteins; Research; Research Personnel; Resources; Sodium; Source; Structure; Synaptic Cleft; Synchrotrons; Testing; Tricyclic Antidepressive Agents; United States National Institutes of Health; Work; base; design; dopamine transporter; drug candidate; gain of function mutation; loss of function mutation; monoamine; neurotransmission; noradrenaline transporter; prevent; psychostimulant; reuptake; serotonin transporter; symporter

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Neurotransmitter:sodium symporters (NSS) regulate neurotransmission at the synaptic cleft through a reuptake mechanism. In this protein family, monoamine transporters including dopamine transporter (DAT), serotonin transporter (SERT) and norepinephrine transporter (NET), are primary targets for antidepressants and psychostimulants. Although the pharmacological effects of these drugs have been studied extensively, little structural information is available, thereby hampering the thorough understanding of the inhibition mechanism and hindering structure based drug design. My current research is focused on studying atomic structures of antidepressants binding sites in neurotransmitter transporters using bacterial homologues. By applying a drug screening strategy called scintillation proximity assay (SPA), We identified a group of drugs that have binding affinity to bacterial transporters. The first drug target desipramine, a tricyclic antidepressant, has been cocrystallized with LeuT, a bacterial amino acid transporter. Homology models of human proteins were built by threading their sequences onto the LeuT-desipramine structure. I further designed both loss-of-function mutations in human SERT and gain-of-function mutations in human DAT to provide strong evidence supporting that the drug binding pockets are probably conserved in human neurotransmitter transporters. The other drug candidates are being test. This work will reveal how different antidepressants block neurotransmitter transporters, prevent conformational changes, and therefore inhibit substrate transport.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 神经递质：钠对菌（NSS）通过再摄取机制在突触裂口处调节神经传递。在该蛋白质家族中，包括多巴胺转运蛋白（DAT），5-羟色胺转运蛋白（SERT）和去甲肾上腺素转运蛋白（NET）的单胺转运蛋白是抗抑郁药和精神刺激剂的主要靶标。尽管已经对这些药物的药理作用进行了广泛的研究，但几乎没有结构信息，从而阻碍了人们对抑制机制和基于阻碍结构的药物设计的彻底理解。 我目前的研究重点是研究使用细菌同源物中神经递质转运蛋白中抗抑郁药结合位点的原子结构。通过应用称为闪烁接近测定（SPA）的药物筛查策略，我们确定了一组与细菌转运蛋白具有结合亲和力的药物。第一个药物靶标脱哌丁胺是一种三环抗抑郁药，已与细菌氨基酸转运蛋白Leut共结合。人类蛋白质的同源性模型是通过将其序列螺纹到Leut-Desipramine结构上的。我进一步设计了人类SERT中的功能丧失突变和人类DAT的功能收益突变，以提供有力的证据，证明药物结合口袋可能是人类神经递质转运蛋白中的保守的。其他候选毒品正在测试。这项工作将揭示不同的抗抑郁药如何阻断神经递质转运蛋白转运蛋白，防止构象变化，从而抑制底物转运。