STRUCTURAL STUDIES OF MULTIDRUG BINDING

多药物结合的结构研究

• 批准号: 7722060
• 负责人: RICHARD GERALD BRENNAN
• 金额: $ 0.02万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7722060
• 关键词: Bacillus subtilis; Binding; Biochemical; Cells; Computer Retrieval of Information on Scientific Projects Database; DNA Binding; Funding; Genes; Genetic Transcription; Grant; Health; Human; Institution; Integral Membrane Protein; Membrane Proteins; Molecular; Multi-Drug Resistance; Numbers; Pharmaceutical Preparations; Poison; Proteins; Research; Research Personnel; Resistance; Resources; Risk; Source; Structure; United States National Institutes of Health; multi drug transporter; mutant; numb protein; pathogen; promoter; response

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Bacterial multidrug resistance (mdr) presents a serious health risk as an increasing number of human pathogens are showing resistance to currently available treatments. One mechanism of mdr involves export of toxic compounds from the cell by multidrug efflux transporters. These membrane proteins have been shown to bind to and efflux a diverse array of structurally and chemically dissimilar compounds. The molecular details of how these transporters recognize and expunge drugs is not fully understood, in part due to the difficulty associated with purifying and crystallizing intrinsic membrane proteins. However, a growing number of proteins have been identified that regulate the expression of multidrug transporters in response to the same toxic compounds that the transporters extrude. These transcriptional regulators are much more amenable to structural and biochemical studies as they are soluble, cytosolic proteins which can be purified more easily and in the quantities that are necessary for structural and biochemical studies. One such transcriptional regulator from Bacillus subtilis, BmrR (bacterial multidrug resistance regulator), activates transcription of the bmr multidrug transporter gene by binding to a plethora of structurally dissimilar lipophilic cationic compounds, many of which are substrates of Bmr. In the absence of drug, BmrR remains bound to the bmr promoter and functions as an anti-activator. Structural studies of BmrR-DNA bound to different inducer molecules along with structures of multidrug binding pocket mutants will help to elucidate the principles by which BmrR can recognize multiple structurally dissimilar drugs.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 随着越来越多的人类病原体对目前可用的治疗方法表现出耐药性，细菌多药耐药(MDR)对健康构成了严重威胁。多药耐药的一种机制涉及通过多药外排转运体将有毒化合物从细胞中输出。这些膜蛋白已被证明与一系列结构和化学上不同的化合物结合并外流。这些转运蛋白如何识别和清除药物的分子细节尚不完全清楚，部分原因是与纯化和结晶内在膜蛋白有关的困难。然而，越来越多的蛋白质被确定为调节多药物转运体的表达，以响应转运体所排出的相同有毒化合物。这些转录调节因子更适合于结构和生化研究，因为它们是可溶性的胞质蛋白，可以更容易地提纯，而且数量是结构和生化研究所必需的。枯草杆菌的一种这样的转录调节因子BmrR(细菌多药耐药调节因子)通过与大量结构不同的亲脂性阳离子化合物结合来激活BMR多药转运蛋白基因的转录，其中许多化合物是BMR的底物。在没有药物的情况下，BmrR仍然与BMR启动子结合，并发挥抗激活剂的作用。BmrR-DNA与不同诱导剂分子结合的结构研究以及多药结合口袋突变体的结构研究将有助于阐明BmrR识别多种结构不同药物的原理。