UNDERSTANDING THE MECHANICS OF ENERGY CONVERSION IN NA+-DEPENDENT CO-TRANSPORTE

了解 NA 相关协同运输中的能量转换机制

• 批准号: 8364190
• 负责人: Michael Grabe
• 金额: $ 0.11万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8364190
• 关键词: Address; Amino Acids; Amino Sugars; Bacteria; Biological Phenomena; Biomedical Research; Childhood; Coupling; Diarrhea; Funding; Galactose; Grant; High Performance Computing; Life; Light; Mammals; Marines; Mechanics; Membrane; Membrane Proteins; Membrane Transport Proteins; Metabolism; Molecular; National Center for Research Resources; Oral Rehydration Therapy; Principal Investigator; Process; Research; Research Infrastructure; Resolution; Resources; Sodium; Source; Structure; Tissues; United States National Institutes of Health; Urea; Vibrio parahaemolyticus; Water; Work; base; cost; molecular dynamics; mortality; small molecule; sugar; symporter

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Membrane transport proteins that utilize a 5-helix inverted repeat motif have recently emerged as the largest structural class of secondary active transporters. These membrane proteins are found throughout all kingdoms of life, and in mammals they are found in all tissues, where they are responsible for transporting small molecules such as amino acids and sugars across membranes. They use electrochemical gradients to concentrate these substrates using an alternating access mechanism originally outlined in the 1950s and 60s (1-3). How this mechanism works at the molecular level is only beginning to be understood as high-resolution structures are being determined. Here, we intend to use molecular dynamics simulations to investigate this process in the sodium-galactose co-transporter (SGLT) from the marine bacterium Vibrio parahaemolyticus, called vSGLT, whose structure was recently solved by our collaborators Drs. Jeff Abramson (UCLA) and Ernie Wright (UCLA) (4). Our proposed work will broadly address the basic biological phenomenon of energy transduction by secondary active transporters. Specifically, it will shed light on sugar metabolism and SGLT associated water transport, the later of which forms the basis of Oral Rehydration Therapy, which is estimated to have decreased childhood mortality due to severe diarrhea from 4.6 million in 1980 to 1.6 million in 2000 (5). We will carry out this work through two specific aims: Specific Aim 1. Characterization of sodium and galactose coupling in vSGLT. Specific Aim 2. Water and urea permeation through vSGLT.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 利用5-螺旋反向重复基序的膜转运蛋白最近已成为二级活性转运蛋白的最大结构类别。这些膜蛋白存在于所有生命界，在哺乳动物中，它们存在于所有组织中，负责跨膜运输小分子，如氨基酸和糖。他们使用电化学梯度来集中这些底物，使用最初在20世纪50年代和60年代概述的交替访问机制（1-3）。随着高分辨率结构的确定，这种机制在分子水平上是如何工作的才刚刚开始被理解。在这里，我们打算使用分子动力学模拟来研究来自海洋细菌副溶血弧菌（Vibrio parahaemolyticus）的钠-半乳糖协同转运蛋白（SGLT）中的这一过程，该细菌称为vSGLT，其结构最近由我们的合作者Jeff Abramson博士（加州大学洛杉矶分校）和Ernie Wright博士（加州大学洛杉矶分校）解决。我们提出的工作将广泛地解决次级主动转运蛋白的能量转导的基本生物现象。具体而言，它将阐明糖代谢和SGLT相关的水运输，后者构成口服补液疗法的基础，据估计，口服补液疗法已将严重腹泻导致的儿童死亡率从1980年的460万降至2000年的160万（5）。我们将通过两个具体目标开展这项工作： 具体目标1. vSGLT中钠和半乳糖偶联的表征。 具体目标2。通过vSGLT的水和尿素渗透。