The structure and function of the beta chemokine receptor D6 - a member of the family of G protein coupled receptors

β趋化因子受体 D6 的结构和功能 - G 蛋白偶联受体家族的成员

• 批准号: BB/D017882/1
• 负责人: Neil William Isaacs
• 金额: $ 95.75万
• 依托单位: University of Glasgow
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2006
• 资助国家: 英国
• 起止时间: 2006 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FD017882%2F1
• 关键词: structure; function; beta; chemokine; receptor

Receptors are proteins embedded in cell membranes with different parts of the molecule extending above and below the membrane surface. When a receptor is bound by its specific ligand on the exterior of the cell, a signal is transmitted to the interior, setting up a chain of events that determine how the cell responds to the signal. Examples are the response of cells when hormones bind to their receptors, or the olefactory response triggered when odour molecules bind receptors in the nose. Since they control the way in which cells respond to external signals, receptors are vitally important in maintaining the well being of the cell. Drugs can bind to receptors and, by their response, influence the biology of the cell. More than half of the drugs in present use interact with receptors. There is a large number of receptors that all have a common structure and similar initial chemical responses to external stimuli. Members of this so-called G-Protein Coupled Receptor (GPCR) family are found acting in situations as diverse as the recognition of taste and odour, responses to tissue damage, mood and behaviour and some cancers. Despite their importance, there is very little knowledge of the three-dimensional structures of GPCRs, owing to the extreme difficulty in extracting the receptors from cells in large enough quantities to purify and crystallise for structural studies. Some years ago we discovered a GPCR, called D6, that binds chemokines (small proteins that are produced in response to tissue damage and stimulate inflammatory responses) and can be produced in relatively large amounts. We can extract and purify D6 and have found a way to grow crystals of D6. We can now determine its 3-dimensional structure using a technique called x-ray crystallography. Once we know the structure of D6 we will be better able to understand how it functions and to design drugs that adapt its biological behaviour. Furthermore, because of the similarity of D6 with other GPCRs, the structure will be very useful as a model for other receptors and provide new insights for further research.

受体是嵌入细胞膜的蛋白质，分子的不同部分在膜表面上下延伸。当受体被细胞外部的特定配体结合时，信号就会传递到细胞内部，从而建立起一系列事件，决定细胞对信号的反应。例如，当激素与其受体结合时，细胞的反应，或者当气味分子与鼻子中的受体结合时，触发的嗅觉反应。因为它们控制着细胞对外界信号的反应方式，所以受体对维持细胞的健康至关重要。药物可以与受体结合，并通过它们的反应影响细胞的生物学。目前使用的药物中有一半以上与受体相互作用。有大量的受体都有一个共同的结构和相似的初始化学反应的外部刺激。这个所谓的G蛋白偶联受体(GPCR)家族的成员被发现在不同的情况下发挥作用，包括对味道和气味的识别，对组织损伤的反应，情绪和行为，以及一些癌症。尽管GPCRs很重要，但人们对GPCRs的三维结构知之甚少，这是因为从细胞中提取足够多的受体来纯化和结晶进行结构研究是极其困难的。几年前，我们发现了一种名为D6的GPCR，它可以结合趋化因子(对组织损伤和刺激炎症反应而产生的小蛋白)，并可以相对大量地产生。我们可以提取和提纯D6，并找到了一种生长D6晶体的方法。我们现在可以使用一种叫做X射线结晶学的技术来确定它的三维结构。一旦我们了解了D6的结构，我们就能更好地理解它的功能，并设计出适应其生物学行为的药物。此外，由于D6与其他GPCRs的相似性，该结构将为其他受体提供非常有用的模型，并为进一步的研究提供新的见解。