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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 我们的项目重点关注细菌 ABC 转运蛋白，它是真核多药耐药 (MDR) 蛋白（例如 P-糖蛋白 (P-gp)）的结构和功能密切同源物。许多针对癌细胞的药物都会诱导 MDR ABC 转运蛋白的过度表达。 MDR ABC 泵会排斥这些药物，从而降低癌症治疗的有效性。为了实现运输，ABC 转运蛋白将 ATP 的结合和水解与其所谓的 ABC（ATP 结合盒）结构域的二聚化和解离结合起来。这些事件触发作为运输机制基础的膜域的构象变化。 迄今为止，我们已经能够收集完整 ABC 转运蛋白 Apo 形式的 4.2 A 分辨率 (X25) 的原始数据。我们目前正在寻找重原子导数，以便对这些原生数据进行定相并求解结构。 该项目的另一部分重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。然而，它们的衍射质量需要提高。 获得 Apo 和 ATP 结合形式的 ABC 转运蛋白的结构应该使我们能够观察触发 ABC 外排转运蛋白（如 P-糖蛋白）转运的构象变化。