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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 细菌多药耐药性（MDR）呈现出严重的健康风险，因为越来越多的人类病原体表现出对当前可用治疗的抵抗力。 MDR的一种机制涉及通过多种外排转运蛋白从细胞中导出有毒化合物。 这些膜蛋白已被证明与结构和化学上不同的化合物结合并排出各种。 这些转运蛋白如何识别和消除药物的分子细节尚未完全理解，部分原因是与纯化和结晶的内在膜蛋白相关的困难。 然而，已经鉴定出越来越多的蛋白质，这些蛋白质会根据转运蛋白挤出的相同有毒化合物的响应来调节多药转运蛋白的表达。 这些转录调节剂更适合于结构和生化研究，因为它们是可溶的，胞质蛋白的，可以更容易地纯化，并且是结构和生化研究所需的数量。 一种从枯草芽孢杆菌（BMRR）（细菌多药耐药调节剂）中的一种此类转录调节剂，通过与多种结构上不同的生物呈阳离子化合物结合，激活BMR多物种转运蛋白基因的转录，其中许多是BMR的基础。 在没有药物的情况下，BMRR保持与BMR启动子的结合，并用作抗激活剂。 BMRR-DNA结合与不同诱导剂分子结合的结构研究以及多药结合袖珍突变体的结构将有助于阐明BMRR可以识别多种结构上不同药物的原理。