Solution NMR spectroscopy studies of an adrenergic receptor b1AR

生物体是由大量的细胞组成的。这些细胞中的每一个都包含对维持和发展特定有机体的生命至关重要的机制。这些细胞被防水的脂质膜包围，脂质膜封装了细胞的主要含水内部，其中还包括基本的分子机器。生命的每一个过程，无论是大规模的还是小规模的，都涉及到对不断变化的环境的不断适应。随着这些变化，并响应通过生物体活动产生的需求，单个细胞内的条件需要不断调整。每个细胞都需要补充能量和建筑材料的营养素，废物需要被清除，需要为众多不同的过程提供指导，以协调一致的方式发挥作用。为了促进这些要求穿过不可穿透的脂质膜，大量蛋白质嵌入细胞膜中。这些蛋白质将细胞外部与细胞内部连接起来，称为膜蛋白。这些蛋白质中的一个特定组负责以控制信号的形式跨膜传递信息。细胞将这些蛋白质用作传感器，将信息从细胞外部传递到细胞内部，然后细胞能够理解需要进行哪些调整。这种控制信号的范围可以是非常多样的，因此有数百个这样的传感器，使其成为一组特别重要的膜蛋白。事实上，它是人类最大的蛋白质家族。我们的工作是更详细地研究这些蛋白质，即所谓的G蛋白偶联受体GPCR。我们试图了解这些蛋白质是如何工作的，特别是给定传感器的不同外部控制信号如何促进细胞内部的不同反应。这些蛋白质暴露在细胞表面使它们很容易接近，这对它们正常工作至关重要。这使得它们也成为药物的理想目标，当我们的身体出现故障并需要药物治疗帮助时。因此，除了了解这些蛋白质如何工作的学术兴趣之外，制药行业对开发更新更好的药物也有很大的兴趣，这些药物将使我们的整体福祉受益。为了能够解决这些问题，通常需要生物学家和化学家使用一系列生物物理技术在分子水平上放大，这使我们能够看到原子尺度上发生了什么。我们的实验室正在使用一种称为核磁共振（NMR）的技术，这使我们能够在接近天然的环境中研究这些GPCR蛋白。为了使这项技术发挥作用，研究中的GPCR被从细胞膜上取下，但仍然被一小部分细胞膜包围着。这些蛋白质非常不稳定，因此研究起来非常棘手。我们正集中在GPCR家族的一个特定成员，它已被修改，并显示出增强的性能，以协助我们的调查。这些传感器蛋白被认为是高度移动的和他们的动态性质强烈影响他们如何发挥作用。NMR是一种很好的方法，可以描述这些蛋白质的哪些部分是灵活的。我们特别感兴趣的是研究这些蛋白质在不同外部信号存在下的迁移率如何变化，以便我们可以将这些变化与细胞内给定的反应相关联。最有可能的是，我们的结果将使我们能够得出非常普遍的结论，因为其他GPCR很可能会以类似的方式发挥作用。到目前为止，GPCR对此类研究来说是难以捉摸的，我们的工作旨在产生这种新颖的见解。

Living organisms are made up of a very large quantity of cells. Each of these cells contains machinery that is essential to maintain and develop the life of a particular organism. These cells are surrounded by a waterproof lipid membrane, which encapsulates the mostly aqueous interior of a cell that includes also the essential molecular machinery. Every process of life both on a large as well as on a small scale involves continuous adaptations to a changing environment. Following such changes and responding to the demands that arise through the activities of the organisms the conditions within the individual cells need to be continuously adjusted. Every cell needs to be supplemented with nutrients for energy and building materials, waste products need to be removed and instructions need to be given for the multitude of different processes to act in a concerted manner. To facilitate these requirements across the impenetrable lipid membrane a large number of proteins are embedded into the cell membrane. These proteins connect the cell exterior with the inside of the cell and are called membrane proteins. A particular group of these proteins is responsible for relaying information in form of control signals across the membrane. The cells are using these proteins as sensors that relay a message from the exterior to the inside of a cell, where a cell is then able to understand what adjustments need to be made. The range of such control signals can be very diverse and there are therefore several hundreds of these sensors making this a particularly important group of membrane proteins. In fact it turns out to be the largest family of proteins in humans. Our work is looking in more details at these proteins, the so-called G protein coupled receptors GPCRs. We are trying to understand how exactly it is that these proteins work and in particular how different external control signals for a given sensor facilitate the different responses on the inside of the cell. Exposure of these proteins on the surface of the cells makes them easily accessible, which is crucial for them to work properly. It makes them also ideal targets for drugs in situations when our body malfunctions and needs drug therapeutic help. Therefore next to the academic interest in understanding how these proteins work there is a large interest from the pharmaceutical industry for the development of newer and better drugs from which our general well being will benefit.To be able to address such questions typically requires biologists and chemists to zoom in on a molecular level using a range of biophysical techniques, which allow us to see what is happening on an atomic scale. Our lab is using a technique called nuclear magnetic resonance (NMR), which allows us to study these GPCR proteins in a nearly native environment. For the technique to work the GPCR under study is removed from the cell membrane but is still kept surrounded by a very small portion of it. These proteins are extremely unstable and hence very tricky to study. We are concentrating on a particular member of the GPCR family, which has been modified and displays enhanced properties to assist our investigations.These sensor proteins are considered to be highly mobile and their dynamic nature strongly influences how they function. NMR is an excellent method that can describe which parts of these proteins are flexible. We are particularly interested in studying how the mobility in these proteins changes in the presence of different external signals so that we can correlate these variations with the given responses inside the cell. Most likely our results will allow us to make conclusions that are very general in nature as it is highly likely that other GPCRs will function following a similar way of action. So far GPCRs have been elusive to such studies and our work intends to generate this novel insight.