Midwest Center for Membrane Protein Structural Dynamics

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。中西部膜蛋白结构动力学中心(MMPSD)是一个高度互动、紧密集成的多学科研究中心，致力于阐明结构、自由能景观、动力学和功能之间的关系。 MMPSD将围绕多学科项目团队组织，调查人员来自中西部地区聚集的机构，以最大限度地实现真正的互动合作和高效的思想交流。这些团队将研究与膜蛋白功能相关的主要机制问题，因为它涉及三个主要领域：信号中的能量转导(离子通道和受体)、能量相互转换(转运体和泵)和化学转导途径(膜嵌入的蛋白酶和磷酸酶)。我们的最终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，MMPSD将同时开发一套工具、概念和试剂来：1)使用伴侣辅助结晶方法确定“原型”膜蛋白的时间平均结构；2)应用最先进的光谱方法(磁共振、荧光)跟踪所确定结构的构象变化和动力学；以及3)设计和实施新颖的计算方法，将静态和动态数据与功能联系起来。四个核心设施将以高度互动的方式与各个项目进行对接和互联。这些核心将通过在四个关键领域提供服务和专业知识来支持中心的研究：膜蛋白表达，建立探针和洗涤剂的化学合成能力，产生各种结晶伴侣和其他靶标结合剂，以及通过元基因组学方法产生一系列新的膜靶标。 所有信息、工具和新试剂/靶标都将通过“膜蛋白质动力学门户”、最先进的网页和一系列对公众开放的科学会议与广大研究人员共享。

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 Midwest Center for Membrane Protein Structural Dynamics (MMPSD) is proposed as a highly interactive, tightly integrated and multidisciplinary effort focused on elucidating the relationship between structure, free energy landscapes, dynamics and function. The MMPSD will be organized around multidisciplinary project teams with investigators from institutions clustered geographically inn [sic] the Midwest to maximize true interactive collaborations and an efficient exchange of ideas. These teams will study major mechanistic questions associated with membrane protein function as it relates to three major areas: energy transduction in signaling (ion channels and receptors) energy interconversion (transporters and pumps) and chemo-transduction pathways (membrane-embedded proteases and phosphatases). Our ultimate goals 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 MMPSD will develop in parallel a set of tools, concepts and reagents to: 1) Determine time-averaged structures of "Archetype" membrane proteins using Chaperone-assisted crystallization methods; 2) Apply state of the art spectroscopic methods (Magnetic Resonance, Fluorescence) to follow conformational changes and dynamics of the determined structures; and 3) Design and implement novel computational approaches to link static and dynamic data with function. Four core facilities will feed and interconnect with the individual projects in a highly interactive way. The cores will support the research in the Center by providing service and expertise in four critical areas: Membrane protein expression, the establishment of chemical synthesis capabilities for probes and detergents, the generation of a large variety of crystallization chaperones and other target binders, and generation of a pipeline of novel membrane targets through metagenomics approaches. All of the information, tools and new reagents/targets will be shared with the research community at large through the "membrane protein dynamics gateway", a state of the art web page and a series of scientific meetings open to the public.