MDR ABC TRANSPORTERS

MDR ABC 转运公司

• 批准号: 7602271
• 负责人: JOHN Francis HUNT
• 金额: $ 1.9万
• 依托单位: BROOKHAVEN SCIENCE ASSOC-BROOKHAVEN LAB
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7602271
• 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.

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