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Bridge 2: Structural Dynamics of ABC Transporter

桥梁 2：ABC Transporter 的结构动力学

基本信息

批准号：
8933657
负责人：
Hassane S Mchaourab
金额：
$ 23.51万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-10 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8933657
关键词：
ABCB1 gene ATP Hydrolysis ATP-Binding Cassette Transporters ATP-binding cassette transport Antineoplastic Agents Base Sequence Binding Biochemical Cell membrane Cholesterol Clinical Collaborations Complement Coupled Coupling Cystic Fibrosis Transmembrane Conductance Regulator Data Set Disease Disulfides Effectiveness Energy Transfer Epilepsy Excretory function Family Fluorescence Fluorescence Resonance Energy Transfer Freezing Goals Human Hydrolysis Immunity Infection Kinetics Malaria Maps Measurement Measures Mechanics Mediating Membrane Proteins Methods Modeling Molecular Molecular Conformation Molecular Machines Monitor Motion Movement Multi-Drug Resistance Mus Mutagenesis Names Nucleotides P-Glycoprotein Pathway interactions Pattern Pharmacologic Substance Phase Physiological Play Population Research Research Personnel Resistance Role Side Spectrum Analysis Staging Structure Testing Time Toxic effect Transmembrane Domain Variant Work absorption base cancer therapy chemotherapy comparative crosslink cytotoxic design efflux pump extracellular human TAP2 protein neoplastic cell novel protein expression protein purification single molecule stem

项目摘要

Multidrug ATP binding cassette (ABC) exporters are ubiquitous ABC transporters that extrude cytotoxic molecules across cell membranes. Mammalian ABC transporters, such as P- glycoprotein (Pgp) and cystic fibrosis transmembrane conductance regulator (CFTR), are exclusively of the exporter class, play critical physiological roles and are associated with disease. Research will continue on the overarching goal of defining the conformational motions that transduce the ATP energy to the mechanical work of substrate translocation by ABC exporters. The design leverages robust methods and approaches, tested and refined by the Cores in phase I of the consortium, to reveal commonalities and differences in the conformational cycles of three archetypes ABC exporters selected based on specific pattern of sequence and mechanistic divergences. The specific aims seek to define the intermediate states required for ATP-powered transport, map the transition pathways and elucidate the kinetics of interconversion between states. An integrated computational and spectroscopic approach capitalizes on the expertise of five investigators, who concurrently participate in the Cores and have a track record of collaboration, to achieve the specific aims. We will use : a novel computational approach to map transition pathways, DEER spectroscopy to monitor domain movements, rapid-freeze quench to time resolve these movements and sm-FRET to detect transient intermediates and measure dwell times. Our findings will be integrated into models in order to reveal how dynamics control the function of ABC exporters.

多药三磷酸腺苷结合盒(ABC)输出体是一种无处不在的ABC转运体细胞毒性分子穿过细胞膜。哺乳动物的ABC转运蛋白，如P- 糖蛋白(Pgp)和囊性纤维化跨膜传导调节因子(CFTR)是完全属于导出器类别，扮演着关键的生理角色，并与疾病。将继续研究确定构象运动的首要目标通过ABC将ATP能量转化为底物转运的机械功出口商。该设计充分利用了健壮的方法和途径，并通过财团第一阶段的核心，以揭示基于特定模式选择的三种原型ABC导出子的构象循环顺序和机制上的分歧。具体的目标试图定义中间体以ATP为动力的运输所需的国家，绘制过渡路径图并阐明态之间相互转化的动力学。一种综合计算和光谱技术该方法利用了五名调查人员的专业知识，他们同时参与了并有合作的记录，以实现具体的目标。我们将使用：a 绘制过渡路径图的新计算方法，监测鹿谱域运动，快速冻结淬火以时间解决这些运动和sm-fret以检测瞬时中间体并测量停留时间。我们的发现将被整合到模型，以揭示动态如何控制ABC出口商的功能。