Project 3 - The Critical Role of Membrane Transport

项目 3 - 膜传输的关键作用

基本信息

批准号：
10242863
负责人：
Robert M Stroud
金额：
$ 52.12万
依托单位：
TEXAS A&M AGRILIFE RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10242863
关键词：
Antibiotics Binding Binding Proteins Biochemical Bioinformatics Biological Assay Categories Cell Wall Cell division Cell membrane Cells Cellular Structures Chemicals Chemistry Collaborations Complex Cryoelectron Microscopy Crystallization Cytoplasm Cytoplasmic Tail Data Drug Targeting Environment Essential Genes Family Fluorescence Genetic Genus Mycobacterium Gram-Negative Bacteria Growth Homologous Gene Hydrophobicity Integral Membrane Protein Iron Lead Length Link Mass Spectrum Analysis Matrix Metalloproteinases Membrane Membrane Proteins Membrane Transport Proteins Metabolism Methods Micronutrients Molecular Structure Mycobacterium Infections Mycobacterium smegmatis Mycobacterium tuberculosis Nodule Nutrient Operon Organism Oxidoreductase Pathway interactions Pharmaceutical Preparations Plasma Process Protein Family Proteins Resistance Resolution Role Siderophores Structure Technology Transmembrane Transport Trehalose Tuberculosis Virulence Virulence Factors X ray diffraction analysis X-Ray Crystallography base design drug development efflux pump falls improved in vivo inhibitor/antagonist lipid transport member mycobacterial mycobactins mycolate next generation pathogen periplasm protein complex protein structure screening small molecule small molecule therapeutics virtual reality environment

项目摘要

Project Summary – Project 3 – Targeting the Critical Role of Membrane Transporters Mtb is an intracellular pathogen and thus is surrounded by a host cell. Because of this immersive environment, Mtb membrane proteins constitute a direct functional interface between the pathogen and its host. They sense the environment and control entry of nutrients and other molecules (including many drugs) into, and exit from the organism. Thus, they offer a ‘gateway’ for small molecule therapeutics. However, to date, there are only two high-resolution structures of Mtb integral membrane proteins due in part to the difficulty of expression, purification and crystallization of membrane proteins, and to the lack of focus onto Mtb. We have developed a general method to prioritize integral membrane proteins identified as viable drug targets, essential genes, or critical virulence factors in Mtb. Our priorities continue to be ranked in collaboration with members of the consortium, using preliminary drug targeting and virulence screening data. Building on our expertise developed as a national center, we have also developed robust methods to express, purify and crystallize integral membrane proteins for structure determination by X-ray crystallography, and by electron cryo-microscopy.

项目摘要 – 项目 3 – 发挥膜转运蛋白的关键作用结核分枝杆菌是一种细胞内病原体，因此被宿主细胞包围。环境中，结核分枝杆菌膜蛋白构成了病原体和结核分枝杆菌之间的直接功能界面。它们感知环境并控制营养物质和其他分子（包括许多分子）的进入。因此，它们为小分子治疗提供了“门户”。然而，迄今为止，Mtb 整合膜蛋白只有两种高分辨率结构。部分原因是膜蛋白的表达、纯化和结晶困难，以及缺乏我们开发了一种优先考虑整合膜蛋白的通用方法。被确定为结核分枝杆菌的可行药物靶点、必需基因或关键毒力因子。将与联盟成员合作，使用初步药物靶向和基于我们作为国家中心开发的专业知识，我们还拥有毒力筛查数据。开发了表达、纯化和结晶完整膜蛋白的稳健方法以用于结构通过 X 射线晶体学和电子冷冻显微镜测定。