Defining the chemical space for ligands of odorant - binding proteins

上一届诺贝尔医学奖授予琳达·巴克和理查德·阿克塞尔，以表彰他们在人类嗅觉方面的工作。人类嗅觉的某些方面很难研究，但在昆虫中，嗅觉更重要，涉及的系统更容易被研究。虽然哺乳动物和昆虫的嗅觉有一些不同，但在许多重要的方面它们是相似的，在这项研究中，我们建议研究果蝇--黑腹果蝇的嗅觉系统。这种昆虫非常适合我们提出的工作，因为这种昆虫的所有遗传信息都已经汇集在一起，而且关于嗅觉对其行为的影响已经知道了很多。此外，我们几乎知道所有的个体气味(大约90种)，每一种都包含一种特定的小分子化学物质，它可以识别这种化学物质。这些小分子化学物质可以被一起带入图书馆，用于这里计划的研究。由于我们拥有这种昆虫完整的遗传信息，我们也知道所有参与嗅觉过程的基因，我们选择了一组这些基因中的一组，这些基因编码参与嗅觉过程第一阶段的蛋白质。这些蛋白质被称为气味结合蛋白(OBP)，这些蛋白质与我们将创建的个体气味化学库的特定成员相互作用。我们计划用单个OBP来搜索这些文库，以找出哪些气味与哪些特定蛋白质相互作用。尽管我们已经使用了几乎所有的气味化合物，但我们也将搜索苍蝇可能与之相互作用的更大数量的其他天然化合物，以寻找任何被遗漏的活性小分子化学物质。对于这些收集，每个包含数百种化合物，我们将从苍蝇可能感兴趣的情况下获取气味，例如，从同一物种的苍蝇或从它们正在腐烂的水果的食物中获取气味。通过允许蛋白质从我们的图书馆和天然产品集合中吸收单独的化合物，将个体气味与特定的OBP联系起来，我们将设计一系列化学物质(我们与OBP匹配的每种气味约为30种)类似于自然气味化合物，但有一些结构上的差异。如果这些化合物仍然与蛋白质相互作用，无论这种相互作用是强还是弱，将使我们能够准确地计算出气味分子必须具有什么样的形状和电荷特征才能成功地与蛋白质相互作用。这将使我们能够改变自然气味，这可能被用来愚弄这些昆虫和其他害虫物种，并提供控制害虫的新方法。此外，我们将研究是否可以使用OBPS来检测作为商业或其他兴趣的关键指标的小分子化合物。例如，当食物开始变质时，会产生一些小分子，在这种材料通常产生的大量小分子中极难检测到，但基于OBPs的设备可以做到这一点，在其他例子中，如检测非法药物和爆炸物。

The last Nobel Prize for Medicine was awarded to Linda Buck and Richard Axel for their work on the sense of smell, called olfaction, in humans. Some aspects of human olfaction are difficult to study, but in insects, where olfaction is even more important, the systems involved are more accessible to investigation. Although there are some differences between olfaction in mammals and insects, in many important ways they are similar and for this study, we propose to work on the olfactory system of the fruit fly, Drosophila melanogaster. This insect is very amenable to our proposed work because all the genetic information for this insect has been assembled and a great deal is known about the influence of olfaction on its behaviour. Also, we know almost all of the individual smells (about 90), each of which comprises a specific small molecular weight chemical, which it recognises. These small molecular weight chemicals can be brought together into libraries for the investigations planned here. Because of the complete genetic information that we have for this insect, we also know all of the genes involved in the olfactory processes and we have selected one set of these genes which code for proteins involved in the first stage of the olfactory process. These proteins are called odorant- binding proteins (OBPs) and these interact with particular members of the chemical libraries of individual smells that we will create. We plan to search these libraries with individual OBPs to find out which smells interact with which particular proteins. Although we have almost all of the smell compounds used, we will also search the much larger collectionss of other natural compounds that the fly may interact with for any active small molecule chemicals that have been missed. For these collections, each containing hundreds of compounds, we will take smells from situations in which the fly is likely to have an interest, for example, from flies of the same species or from their food, which is rotting fruit. Having linked individual smells to particular OBPs by allowing the protein to absorb individual compounds from our libraries and natural product collections, we will design ranges of chemicals (about 30 for each of the smells that we have matched to an OBP) that are similar to the natural smell compounds but with some structural differences. If these compounds still interact with the protein, and whether this interaction is stronger or weaker, will allow us to work out exactly what shape and electronic charge characteristics the smell molecule must have to interact successfully with the protein. This will allow us to make alterations to the natural smells, which could be used to fool these insects and other pest insect species and offer new ways to control insect pests. In addition, we will investigate whether we can use OBPs to detect small molecular weight compounds that act as key indicators of commercial or other interest. For example, when food begins to deteriorate, some small molecules are produced which are extremely difficult to detect amongst the large amounts of small molecules normally produced by this material, but a device based on OBPs could do this and in other examples, such as the detection of illegal drugs and explosives.