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The Neurotransmitter: Sodium Symporter Permeation Pathway

神经递质：钠转运蛋白渗透途径

基本信息

批准号：
7640664
负责人：
Lei Shi
金额：
$ 9万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7640664
关键词：
Affect Amino Acids Amphetamines Antidepressive Agents Bacteria Binding Binding Sites Biochemical Biogenic Amines Biological Models Brain Carrier Proteins Cocaine Data Dental Cavity Lining Development Dissociation Docking Dopamine Drug Design Electron Spin Resonance Spectroscopy Engineering Environment Equilibrium Family Fusobacterium nucleatum Genes Genome Glycine Goals Homologous Gene Human Humulus Imipramine In Vitro Informatics Information Management Investigation Ions Kinetics Knowledge Leucine Ligand Binding Light Literature Membrane Methods Modeling Molecular Molecular Conformation Molecular Models Molecular Target Monitor Mutagenesis Mutation Neurotransmitters Norepinephrine Pathway interactions Pharmaceutical Preparations Play Positioning Attribute Procedures Process Prokaryotic Cells Property Protein Family Proteins Protocols documentation Publications Recycling Research Personnel Resolution Rewards Role Route Scheme Serotonin Signal Transduction Site Sodium Solid Specificity Spin Labels Structure Structure-Activity Relationship Substrate Specificity System Testing Tryptophan Tyramine Tyrosine Validation Work base comparative design dopamine transporter extracellular gamma-Aminobutyric Acid member models and simulation molecular dynamics molecular modeling molecular transporter multidisciplinary neurotransmission noradrenaline transporter novel presynaptic programs protein transport psychostimulant receptor research study serotonin transporter simulation sodium ion symporter text searching therapeutic target tool uptake

项目摘要

DESCRIPTION (provided by applicant): Biogenic amine transporters play important roles in the action and recycling of their specific neuretransmitter substrates. They have been well established as the targets for many pharmacological agents that affect brain function. For examples, the rewarding properties of cocaine 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 NeurotransmitterSodium Symporter (NSS) family, which has a large number of prokaryotic homologs, including a tryptophan transporter (TnaT), a tyrosine transporter (Tyt1), and a leucine transporter (LeuT). Recently, a 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 the substrate hopping model. Specifically, using prokaryotic NSS-proteins, TnaT, Tyt1, and LeuT 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 TnaT/Tyt1/LeuT, and with other 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.

描述（由申请人提供）：生物胺转运蛋白在其特定神经递质底物的作用和回收中发挥重要作用。它们已被确定为许多影响大脑功能的药物的靶标。例如，可卡因的有益特性主要是由于它对多巴胺转运蛋白（DAT）的抑制作用；丙咪嗪的抗抑郁作用是通过血清素转运蛋白（SERT）发挥作用的。这些转运蛋白属于神经递质钠转运蛋白（NSS）家族，该家族具有大量原核同源物，包括色氨酸转运蛋白（TnaT）、酪氨酸转运蛋白（Tyt1）和亮氨酸转运蛋白（LeuT）。最近，我们以高分辨率解析了 LeuT 结构，其中底物 Leu 结合在封闭的空腔中。然而，底物特异性的决定因素（了解底物特异性对于合理的药物设计非常重要）可能不仅位于 LeuT 结构揭示的结合位点缝隙内，而且还位于渗透途径中。本提案的长期目标是阐明易位周期期间 NSS 家族蛋白渗透途径的动态结构变化，并评估竞争性运输模型，例如。例如，交替访问方案和衬底跳跃模型。具体来说，使用原核 NSS 蛋白、TnaT、Tyt1 和 LeuT 作为模型系统，这将通过分子建模模拟和实验研究/验证之间的集成、比较迭代过程来实现。通过这个多学科协议，我们将探索保守的残基位置和潜在的辅助空腔，它们沿着渗透路径并在不同的构象状态下动态重组。将比较 TnaT/Tyt1/LeuT 以及其他原核和真核 NSS 蛋白的渗透途径的共同特征和不同特征，包括钠离子的作用。所获得的知识应该有助于阐明生物胺转运蛋白的易位循环，并将有助于我们理解底物特异性的结构基础。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

R-modafinil (armodafinil): a unique dopamine uptake inhibitor and potential medication for psychostimulant abuse.

DOI：
10.1016/j.biopsych.2012.03.022
发表时间：
2012-09-01
期刊：
BIOLOGICAL PSYCHIATRY
影响因子：
10.6
作者：
Loland, Claus J.;Mereu, Maddalena;Okunola, Oluyomi M.;Cao, Jianjing;Prisinzano, Thomas E.;Mazier, Sonia;Kopajtic, Theresa;Shi, Lei;Katz, Jonathan L.;Tanda, Gianluigi;Newman, Amy Hauck
通讯作者：
Newman, Amy Hauck

The sodium/multivitamin transporter: a multipotent system with therapeutic implications.