MDR ABC TRANSPORTERS

MDR ABC 转运公司

• 批准号: 7726204
• 负责人: JOHN Francis HUNT
• 金额: $ 2.41万
• 依托单位: BROOKHAVEN SCIENCE ASSOC-BROOKHAVEN LAB
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-18 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7726204
• 关键词: ATP Hydrolysis; ATP-Binding Cassette Transporters; Binding; Computer Retrieval of Information on Scientific Projects Database; Data; Dimerization; Dissociation; Drug Delivery Systems; Effectiveness; Event; Funding; Grant; Homologous Gene; Institution; Membrane; Multi-Drug Resistance; P-Glycoprotein; P-Glycoproteins; Pharmaceutical Preparations; Phase; Proteins; Pump; Range; Research; Research Personnel; Resolution; Resources; Source; Structure; United States National Institutes of Health; base; cancer cell; cancer therapy; improved

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. Our project focusses on a bacterial ABC transporter that is a close structural and functional homologue of eukaryotic multi-drug resistance (MDR) proteins such as P-glycoprotein (P-gp). A broad range of drugs that target cancer cells induce the over-expression of MDR ABC transporters. MDR ABC pumps reject these drugs and therefore reduce the effectiveness of cancer treatments. To achieve transport, ABC transporters couple the binding and hydrolysis of ATP to the dimerization and dissociation of their so-called ABC (ATP binding cassette) domains. These events trigger conformational changes in the membrane domains that are at the basis of the transport mechanism. To date, We have been able to collect native data to 4.2 A resolution (X25) for an Apo form of the complete ABC transporter. We are currently looking for heavy atom derivatives in order to phase these native data and solve the structure. Another part of the project foccusses on solving the structure of an ATP-bound form of this transporter. We have been able to obtain crystals of such a form. However, their diffraction quality need to be improved. Obtaining structures of this ABC transporter in both Apo and ATP-bound forms should allow us to observe the conformational changes triggering transport in ABC efflux transporters such as P-glycoprotein.

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。 我们的项目集中在细菌ABC转运蛋白上，该转运蛋白是真核多药耐药性（MDR）蛋白（如P-糖蛋白（P-gp））的紧密结构和功能同源物。靶向癌细胞的广泛药物会诱导MDR ABC转运蛋白的过表达。 MDR ABC泵拒绝这些药物，因此降低了癌症治疗的有效性。为了实现运输，ABC转运蛋白将ATP的结合和水解与所谓的ABC（ATP结合盒）域的二聚和解离。这些事件触发了基于运输机制的膜结构域中的构象变化。 迄今为止，我们已经能够为完整ABC转运蛋白的APO形式收集本机数据为4.2分辨率（X25）。目前，我们正在寻找沉重的原子衍生物，以便对这些天然数据进行分配并解决结构。 该项目的另一部分焦点是解决该转运蛋白的ATP结合形式的结构。我们已经能够获得这种形式的晶体。但是，它们的衍射质量需要提高。 在APO和ATP结合形式中获得该ABC转运蛋白的结构应使我们能够观察到触发ABC外排转运蛋白（如P-糖蛋白）中转运的构象变化。