The structural basis of cell surface receptor signalling mechanisms.

多细胞生物体的细胞，如人类，在发育过程中必须经过精致的编排。在发育中的生物体中，每个细胞必须在特定的时间和地点达到与其角色相适应的粘附性和运动性之间的特殊平衡。指导每个细胞的许多信息必须通过与其邻近环境包括邻近细胞的相互作用而获得。这些相互作用是由嵌入在细胞表面的各种类型的受体分子介导的。我们希望了解几组受体是如何共同作用来控制细胞粘着(粘着)或沿特定方向移动的能力。利用结构生物学技术，我们的目标是以原子细节展示受体控制细胞黏附和引导的机制，例如在指导大脑连接的系统中。这些机制必须整合发生在细胞之间和同一细胞表面上的受体相互作用，以及从细胞外环境到细胞内环境的相互作用。为了深入了解这种系统，我们需要使用在我们之前的MRC资助的研究中开发的最先进的技术来产生合适的跨受体和复合体的膜样本，并将对分离分子的体外结构研究与细胞表面功能相关的原位分析结合起来。最终，我们可能会利用我们揭示的机制来修复神经损伤或治疗各种神经疾病。

The cells of a multicellular organism, such as a human, must be subject to an exquisite choreography during development. Each cell must achieve the particular balance between adhesion and motility appropriate to its role at a specific time and place in the developing organism. Much of the information to direct each cell must be garnered through interaction with its immediate environment including neighbouring cells. These interactions are mediated by various types of receptor molecules embedded in the cell surface. We wish to understand how sets of receptors work together to control the ability of a cell to stick (adhere) or to move in a specific direction. Using the techniques of structural biology we aim to show in atomic detail the mechanisms by which receptors control cell adhesion and guidance, for example in a system which directs the wiring of the brain. These mechanisms must integrate receptor interactions occurring between cells and on the same cell surface, as well as spanning from the extracellular to the intracellular environment. To generate insight into such systems we will need to use state of the art techniques developed during our previous MRC funded studies to produce suitable samples of membrane spanning receptors and complexes and to combine in vitro structural studies on the isolated molecules with in situ analyses in the functionally relevant context of the cell surface. Ultimately it may prove possible to exploit the mechanisms we reveal to repair nerve damage or to treat various neurological disorders.