Membrane Protein Structural Dynamics Consortium

描述(由申请人提供)：膜蛋白在控制物质和信息进出细胞、决定能量的流动和使用以及触发许多信号通路的启动方面发挥着重要作用。为了完成这些角色，构象和相互作用动力学对它们的功能行为起着主导作用，因为结构和动力学之间的相互作用最终决定了它们的功能。膜蛋白结构动力学联合会(MPSDC)是一个高度互动、紧密集成的多学科研究机构，致力于阐明各种膜蛋白的结构、动力学和功能之间的关系。 MMPSD将围绕来自五个不同国家的14个机构的调查人员组成的多学科项目小组进行组织。这些团队将研究与膜蛋白功能相关的主要机制问题，因为它涉及两个主要领域：信号中的能量转导(离子通道和受体)和能量相互转换(转运体和泵)。最终，我们的目标是通过在前所未有的定量水平上剖析和分析这些功能的分子和动力学基础，以及利用这些信息将改变的和新的活动工程到膜蛋白质框架中，从而合理地进化新的功能，来破译支配蛋白质运动及其相关波动动力学的一般机制原理。为了实现其目标，MPSDC将同时开发一套工具、概念和试剂，以：1)应用最先进的光谱方法(磁共振、荧光、2D-IR)跟踪所确定结构的构象变化和动力学；2)将动态测量与高分辨率系综和单分子功能测量相关联；以及3)设计和实施新的计算方法，将静态和动态数据与功能联系起来。六个核心设施将以高度互动的方式与单个项目对接和互联。这些核心将同时充当“创新孵化器”和研究支持中心，在下列关键领域提供服务和专业知识：膜蛋白表达，建立探针和洗涤剂的化学合成能力，产生各种结合剂和其他结晶伴侣及其他靶标结合剂，开发通用计算工具来解释和整合丰富的实验数据，产生新颖的、高度专一性的合成毒素，以及通过使用元基因组学工具不断发现新的靶标。

DESCRIPTION (provided by applicant): Membrane proteins play an essential role in controlling the movement of material and information in and out of the cell, in determining the flow and use of energy, as well as in triggering the initiation of numerous signaling pathways. To fulfill these roles, conformational and interaction dynamics exert a dominant influence on their functional behavior, for it is the interplay between structure and dynamics what ultimately defines their function. The Membrane Protein Structural Dynamics Consortium (MPSDC) is proposed as a highly interactive, tightly integrated and multidisciplinary effort focused on elucidating the relationship between structure, dynamics and function in a variety of membrane proteins. The MMPSD will be organized around multidisciplinary project teams formed by investigators from 14 institutions in five different countries. These teams will study major mechanistic questions associated with membrane protein function as it relates to two major areas: energy transduction in signaling (ion channels and receptors) and energy inter-conversion (transporters and pumps). Ultimately, our goal is to decode the general mechanistic principles that govern protein movement and its associated fluctuation dynamics by dissecting and analyzing the molecular and dynamical bases of these functions at an unprecedented and quantitative level, as well as exploiting this information to engineer altered and novel activities into membrane protein frameworks to rationally evolve new functions. To accomplish its goals, the MPSDC will develop in parallel a set of tools, concepts and reagents to: 1) Apply state of the art spectroscopic methods (Magnetic Resonance, Fluorescence, 2D-IR) to follow conformational changes and dynamics of the determined structures; 2) Correlate dynamic measurements with high-resolution ensemble and single molecule functional measurements; and 3) Design and implement novel computational approaches to link static and dynamic data with function. Six core facilities will feed and interconnect with the individual projects in a highly interactive way. The cores will act as both, "innovation incubators" and research support centers by providing service and expertise In these critical areas: Membrane protein expression, the establishment of chemical synthesis capabilities for probes and detergents, the generation of a variety of binders and other crystallization chaperones and other target binders, the development of common computational tools to interpret and integrate the wealth of experimental data, the generation of novel, highly specific synthetic toxins and the continuous discovery of novel targets through the use of metagenomics tools.