Structural studies of a bacterial membrane bound antibiotic transporter

细菌膜结合抗生素转运蛋白的结构研究

• 批准号: BB/H01778X/1
• 负责人: Konstantinos Beis
• 金额: $ 45.87万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2010
• 资助国家: 英国
• 起止时间: 2010 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FH01778X%2F1
• 关键词: Structural; studies; bacterial; membrane; bound

Membrane proteins represent around 30% of the proteomes of most organisms and more than 40% of drug targets and yet few structures of these molecules have been solved by X-ray crystallography. Bacterial membrane proteins are essential for antibiotic resistance since they are involved in the export of the drugs from the cell. These proteins are usually embedded in oil like environment making them very difficult to work with. We first need to isolate them from the membrane using lipid mimics such as detergents. Membrane proteins usually have many functions and bacteria have developed mechanisms to utilise them in order to extrude antibiotics through these proteins. Understanding the structure and function of these important biological molecules will contribute to the understanding of the relationship between membrane protein and substrate recognition and provide valuable information to structural biology and pharmacology. In order to gain a detailed understanding of the mechanism of these proteins we need to grow crystals and expose them to X-rays in order to obtain the molecular structure. We have obtained such crystals of a bacterial membrane protein antibiotic transporter. The structural information of this membrane protein will provide an important insight on the binding and recognition of antibiotics from this new family of proteins. We are also going to understand the biochemistry of this protein in the presence of antibiotics. Having all these information, the structure and biochemical analysis, will have pharmacological importance since it will allow the development of novel antibiotics that can fight bacterial resistance.

膜蛋白占大多数生物体蛋白质组的30%左右，占药物靶点的40%以上，但这些分子的结构很少被X射线晶体学解决。细菌膜蛋白是抗生素耐药性所必需的，因为它们参与了药物从细胞中的输出。这些蛋白质通常嵌入在油样环境中，使它们非常难以处理。我们首先需要使用脂质模拟物如去污剂将它们从膜上分离出来。膜蛋白通常具有许多功能，细菌已经开发出利用它们的机制，以便通过这些蛋白质挤出抗生素。了解这些重要生物分子的结构和功能将有助于了解膜蛋白与底物识别的关系，并为结构生物学和药理学提供有价值的信息。为了详细了解这些蛋白质的机制，我们需要生长晶体并将其暴露于X射线以获得分子结构。我们已经获得了这种细菌膜蛋白抗生素转运蛋白的晶体。这种膜蛋白的结构信息将提供一个重要的洞察力，从这个新的蛋白质家族的抗生素的结合和识别。我们还将了解这种蛋白质在抗生素存在下的生物化学。拥有所有这些信息，结构和生化分析，将具有药理学重要性，因为它将允许开发可以对抗细菌耐药性的新型抗生素。

项目成果

Structural basis for hijacking siderophore receptors by antimicrobial lasso peptides.

• DOI: 10.1038/nchembio.1499
• 发表时间: 2014-05
• 期刊: NATURE CHEMICAL BIOLOGY
• 影响因子: 14.8
• 作者: Mathavan, Indran;Zirah, Severine;Mehmood, Shahid;Choudhury, Hassanul G.;Goulard, Christophe;Li, Yanyan;Robinson, Carol V.;Rebuffat, Sylvie;Beis, Konstantinos
• 通讯作者: Beis, Konstantinos