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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

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

一、资助父母奖总结r01 gm140584