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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：
9149305
负责人：
Hassane S Mchaourab
金额：
$ 16.37万
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
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9149305
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 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 ATP 结合盒 (ABC) 输出蛋白是普遍存在的 ABC 转运蛋白，可挤出细胞毒性分子穿过细胞膜。哺乳动物 ABC 转运蛋白，例如 P- 糖蛋白 (Pgp) 和囊性纤维化跨膜电导调节因子 (CFTR) 专门属于出口商类别，发挥重要的生理作用，并与疾病。研究将继续以定义构象运动为总体目标通过 ABC 将 ATP 能量转换为底物易位的机械功出口商。该设计利用了稳健的方法和途径，并由该联盟第一阶段的核心，旨在揭示各领域的共性和差异根据特定模式选择的三种原型 ABC 输出者的构象循环顺序和机制上的分歧。具体目标旨在定义中间 ATP 驱动的运输所需的状态，绘制过渡路径并阐明状态之间相互转换的动力学。综合计算和光谱该方法利用了五位研究人员的专业知识，他们同时参与核心并拥有合作记录，以实现特定目标。我们将使用：绘制转变路径的新颖计算方法，监测 DEER 光谱域运动，快速冷冻淬灭以时间解决这些运动和 sm-FRET 检测瞬态中间体并测量停留时间。我们的研究结果将被整合到模型以揭示动态如何控制 ABC 出口商的功能。