AMINO ACID TRANSPORTER

氨基酸转运蛋白

• 批准号: 8170613
• 负责人: CHRISTOPHER CHARLES LAW
• 金额: $ 0.39万
• 依托单位: BROOKHAVEN SCIENCE ASSOC-BROOKHAVEN LAB
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8170613
• 关键词: Affinity; Amino Acid Transporter; Antidepressive Agents; Binding; Binding Sites; Biological Assay; Computer Retrieval of Information on Scientific Projects Database; Desipramine; Drug Delivery Systems; Funding; Grant; Homologous Gene; Homology Modeling; Human; Institution; Neurotransmitters; Pharmaceutical Preparations; Preclinical Drug Evaluation; Protein Family; Proteins; Research; Research Personnel; Resources; Sodium; Source; Structure; Synaptic Cleft; 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.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 神经递质：钠同向转运体（NSS）通过再摄取机制调节突触间隙的神经传递。在这个蛋白质家族中，单胺转运蛋白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），是抗抑郁药和精神兴奋剂的主要靶点。虽然这些药物的药理作用已被广泛研究，但很少有结构信息，从而阻碍了对抑制机制的深入了解，阻碍了基于结构的药物设计，我目前的研究重点是利用细菌同系物研究神经递质转运体中抗抑郁药结合位点的原子结构。通过应用闪烁邻近分析（SPA）的药物筛选策略，我们鉴定了一组与细菌转运蛋白具有结合亲和力的药物。第一个药物靶点地昔帕明是一种三环类抗抑郁药，已与细菌氨基酸转运蛋白LeuT共结晶。人类蛋白质的同源模型是通过将它们的序列连接到LeuT-地昔帕明结构上来构建的。我进一步设计了人SERT中的功能丧失突变和人DAT中的功能获得突变，以提供强有力的证据支持药物结合口袋可能在人神经递质转运蛋白中是保守的。其他候选药物正在测试中。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，防止构象变化，从而抑制底物转运。