Project 3 - The Critical Role of Membrane Transport

项目 3 - 膜传输的关键作用

• 批准号: 10456893
• 负责人: Robert M Stroud
• 金额: $ 51.85万
• 依托单位: TEXAS A&M AGRILIFE RESEARCH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10456893
• 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; lipid transport; member; mycobacterial; mycobactins; mycolate; next generation; pathogen; periplasm; protein complex; protein structure; screening; small molecule; small molecule therapeutics; virtual reality environment

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.

项目概要-项目3 -针对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。由于这种身临其境的 在环境中，Mtb膜蛋白构成了病原体和 它的宿主它们感知环境并控制营养物质和其他分子（包括许多 药物）进入和离开生物体。因此，它们为小分子治疗提供了“门户”。 然而，到目前为止，只有两个高分辨率结构的结核分枝杆菌整合膜蛋白，由于在 一部分是由于膜蛋白的表达、纯化和结晶困难，另一部分是由于缺乏 关注结核病我们已经开发了一种通用的方法来优先考虑整合膜蛋白 确定为Mtb中可行的药物靶点、必需基因或关键毒力因子。我们的优先事项继续 与联盟成员合作进行排名，使用初步药物靶向， 毒力筛选数据。基于我们作为国家中心发展的专业知识，我们还 开发了强大的方法来表达，纯化和结晶完整的膜蛋白的结构 通过X射线晶体学和电子冷冻显微镜测定。