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基本信息

批准号：
10623041
负责人：
Heather Wendy Pinkett
金额：
$ 7.85万
依托单位：
NORTHWESTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10623041
关键词：
ATP-Binding Cassette Transporters Adenosine Triphosphate Affinity Antibiotic Resistance Antibiotics Award Bacteria Binding Binding Proteins Biochemical Bioinformatics Biological Assay Biological Models Biophysics Carrier Proteins Cell Survival Cell membrane Cells Classification Scheme Complex Computer Models Core Assembly Coupled Cues Cytoplasm DSPP gene Data Dipeptides Docking Electrophoretic Mobility Shift Assay Ensure Environment Escherichia coli Family Funding Gatekeeping Genome Glutathione Goals Haemophilus influenzae Heme Heme Iron Hydrolysis Immune In Vitro Inflammation Laboratories Membrane Molecular Nickel Nontypable Haemophilus influenza Nucleotides Nutrient Oligopeptides Operon Organism Otitis Media Parents Pasteurellaceae Peptide Transport Peptides Play Prevalence Production Proteins Regulation Research Research Personnel Respiratory Disease Respiratory System Rice Role SH2D1A gene Series Source Specificity Starvation Surface Plasmon Resonance System Testing Therapeutic Time Tissues Toxin Transmembrane Domain Virulence Factors Work World Health Organization antimicrobial peptide base cofactor comparative experimental study gene cloning graduate student heme a heme-binding protein host colonization in silico in vivo insight middle ear mutant novel parent grant pathogen pathogenic bacteria periplasm programs resistance mechanism structural biology uptake

ATP-Binding Cassette Transporters Adenosine Triphosphate Affinity Antibiotic Resistance Antibiotics Award Bacteria Binding Binding Proteins Biochemical Bioinformatics Biological Assay Biological Models Biophysics Carrier Proteins Cell Survival Cell membrane Cells Classification Scheme Complex Computer Models Core Assembly Coupled Cues Cytoplasm DSPP gene Data Dipeptides Docking Electrophoretic Mobility Shift Assay Ensure Environment Escherichia coli Family Funding Gatekeeping Genome Glutathione Goals Haemophilus influenzae Heme Heme Iron Hydrolysis Immune In Vitro Inflammation Laboratories Membrane Molecular Nickel Nontypable Haemophilus influenza Nucleotides Nutrient Oligopeptides Operon Organism Otitis Media Parents Pasteurellaceae Peptide Transport Peptides Play Prevalence Production Proteins Regulation Research Research Personnel Respiratory Disease Respiratory System Rice Role SH2D1A gene Series Source Specificity Starvation Surface Plasmon Resonance System Testing Therapeutic Time Tissues Toxin Transmembrane Domain Virulence Factors Work World Health Organization antimicrobial peptide base cofactor comparative experimental study gene cloning graduate student heme a heme-binding protein host colonization in silico in vivo insight middle ear mutant novel parent grant pathogen pathogenic bacteria periplasm programs resistance mechanism structural biology uptake

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项目摘要

I. SUMMARY OF THE FUNDED PARENT AWARD R01 GM140584 This proposal seeks to understand how proteins located in the cell membrane work as gatekeepers to selectively allow compounds into or out of the cell. Such gatekeepers are known as ATP-binding cassette (ABC) transporters because they use the energy of ATP (adenosine triphosphate) hydrolysis to transport compounds across the cell membrane. Bacterial ABC importers are essential for organism survival, controlling the rate of uptake for nutrients scavenged from the bacterium's environment. Control of the rate of transport precludes over- accumulation of a nutrient that is beneficial at low concentrations but is potentially toxic at high concentrations. While a subset of ABC proteins contain an additional “accessory” domain that can regulate the uptake of compounds by shutting off the transporter, it is unclear why certain transporters contain these domains while others do not. However, we do understand that certain transporters are “turned off” when a specific compound or protein binds to this accessory domain. Other accessory domains regulate by “sensing” changes in the microenvironment and reacting accordingly. To decipher this mechanism of regulation, the PI's laboratory combines biochemical and biophysical experiments with structural biology to understand how these accessory domains play a role in transport regulation, which in restricts or allows nutrients to enter the cell. This research program will define the molecular mechanism that controls nutrient uptake and allow researchers to understand how multiple transport systems work in concert within an organism to maintain cell survival. We will test our hypothesis that regulation of transporter activation via a sensing accessory protein. The proposed research will decipher the complex circuitry of regulation in a model system in three Aims to: (1) understand how PepT SBPs select for different substrates within the microenvironment (i.e., nutrients, cofactors, and peptides); (2) determine how the assembly of the core transporter dictates transport selectivity and efficiency (3) reveal how PepT transporters regulate the import of substrates into the cell through the activation of a novel regulatory domain. This research program has set out to close critical gaps in the understanding of the fundamentals of the transport mechanism present in all bacteria. The results will yield insights into how regulatory domains modulate transport across all organisms, crucial for cell viability. There are no changes to the funded parent award

I.资助的父母奖R01 GM140584的摘要该建议旨在了解蛋白质如何位于细胞膜工作中，作为看门人有选择地允许化合物进入或退出细胞。这样的网守被称为ATP结合盒（ABC）转运蛋白是因为它们利用ATP（三磷酸腺苷）水解的能量转运化合物穿过细胞膜。细菌ABC进口商对于有机体生存至关重要，控制了吸收从细菌环境中清除的营养物质。控制运输速率的控制无法超出在低浓度下有益但在高浓度下具有毒性的营养素的积累。虽然ABC蛋白的子集包含一个其他“附件”域，该域可以调节化合物通过关闭转运蛋白，目前尚不清楚某些转运蛋白为什么包含这些域而其他人没有。但是，我们确实知道，当特定化合物时，某些转运蛋白被“关闭” 或蛋白质与该附件结构域结合。其他附件域通过“传感”变化而调节微环境并做出相应的反应。为了破译这种监管机制，PI的实验室将生化和生物物理实验与结构生物学相结合，以了解这些附件如何域在运输调节中发挥作用，该调节在限制或允许营养进入细胞中。这项研究程序将定义控制营养摄取的分子机制，并允许研究人员理解多个运输系统如何在组织内部协同工作以维持细胞生存。我们将测试我们的假设通过灵敏度辅助蛋白调节转运蛋白激活。拟议的研究将在三个目的中，在模型系统中解释了复杂的调节电路：（1）了解pept sbps如何选择微环境内的不同底物（即营养，辅助因子和胡椒粉）；（2）确定核心转运蛋白的组装如何决定运输选择性和效率（3）转运蛋白通过新的调节结构域的激活来调节底物进口到细胞中。该研究计划已开始在理解运输基础的理解方面弥合关键差距所有广播中存在的机制。结果将产生有关调节域如何调节运输的见解在所有生物体中，对细胞生存能力至关重要。资助的父母奖没有变化