The Neurotransmitter: Sodium Symporter Permeation Pathway

神经递质：钠转运蛋白渗透途径

• 批准号: 8288299
• 负责人: Lei Shi
• 金额: $ 23.44万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 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 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8288299
• 关键词: Affect; Amphetamines; Antidepressive Agents; Binding; Binding Sites; Biogenic Amines; Biological Models; Brain; Cocaine; Dental Cavity Lining; Drug Design; Equilibrium; Family; Goals; Homologous Gene; Imipramine; Instruction; Investigation; Knowledge; Leucine; Light; Location; Modeling; Molecular; Molecular Conformation; Molecular Models; Monitor; Mutation; Neurotransmitters; Pathway interactions; Play; Positioning Attribute; Process; Property; Protein Dynamics; Protein Family; Proteins; Protocols documentation; Recycling; Resolution; Rewards; Role; Scheme; Sodium; Solid; Structure; Substrate Specificity; Techniques; Testing; Validation; base; comparative; dopamine transporter; drug of abuse; models and simulation; molecular modeling; multidisciplinary; serotonin transporter; sodium ion; symporter; therapeutic target

Biogenic amine transporters play important roles in the action and recycling of their specific neurotransmitter substrates. They have been well established as the targets for many pharmacological agents that affect brain function. For examples, the rewarding properties ofthe abused drugs, cocaine and amphetamine, are due mainly to its inhibition of dopamine transporter (DAT); the antidepressant effect of imipramine is exerted on serotonin transporter (SERT). These transporters belong to the Neurotransmitter:Sodium Symporter (NSS) family, which has a large number of prokaryotic homologs. A prokaryotic leucine transporter (LeuT) structure has been solved in high resolution, with the substrate Leu bound in an enclosed cavity. However, the determinants of substrate specificity, an understanding of which is important for rational drug design, may lie not only within the binding site crevice revealed by the LeuT structure, but also along the permeation pathway. The long term goal of the present proposal is to elucidate dynamic structural changes of the permeation pathway of NSS family proteins during the translocation cycle and to evaluate competing transport models, e. g., the alternating-access scheme and our two-substrate model. Specifically, using prokaryotic NSS-proteins as model systems, this will be achieved by an integrated, comparative process of iteration between molecular modeling simulations and experimental investigations/validations. With this multidisciplinary protocol we will explore the conserved residue positions and potential auxiliary cavities that line the permeation pathway and reorganize dynamically in different conformational states. The common, and the different features of the permeation pathways, including the roles of sodium ions, will be compared among prokaryotic and eukaryotic NSS-proteins. The knowledge acquired should shed light on the translocation cycles of biogenic amine transporters and will contribute to our understanding of the structural bases of substrate specificities.

生物胺转运体在其特异性神经递质的作用和循环中起着重要作用 印刷受体.它们已被公认为许多药理学药物的靶点， 大脑功能例如，可卡因和安非他明等滥用药物的奖励特性是 主要是由于其抑制多巴胺转运蛋白（DAT）;丙咪嗪的抗抑郁作用是发挥 5-羟色胺转运体（SERT）这些转运体属于神经递质：钠同向转运体 (NSS)家族，其中有大量的原核同源物。原核亮氨酸转运蛋白（LeuT） 结构已经解决了高分辨率，与基板Leu约束在一个封闭的空腔。然而，在这方面， 底物特异性的决定因素，理解这一点对于合理的药物设计很重要， 可能不仅位于LeuT结构所揭示的结合位点缝隙内，而且还沿着渗透 通路本提案的长期目标是阐明 NSS家族蛋白在易位周期中的渗透途径，并评估竞争性渗透途径。 运输模型，e.例如，在一个实施例中，交替存取方案和我们的双衬底模型。具体来说，使用 原核NSS蛋白作为模型系统，这将通过一个综合的，比较的过程来实现， 分子建模模拟和实验研究/验证之间的迭代。与此 多学科的协议，我们将探讨保守的残基位置和潜在的辅助腔， 排列渗透途径，并在不同的构象状态下动态重组。普通的， 并比较了不同渗透途径的特点，包括钠离子的作用 在原核和真核NSS蛋白中。所获得的知识应该有助于了解 易位周期的生物胺转运蛋白，并将有助于我们了解的结构 底物特异性的基础。