Molecular basis of olfactory perception.

描述(申请人提供)：疟疾是世界上最具破坏性的疾病之一，每年造成100-200万人死亡。疟疾是通过感染疟疾寄生虫的雌性蚊子的叮咬传播的。冈比亚按蚊的雌性蚊子几乎完全以人类为食，并利用人类汗液和皮肤中存在的气味来定位它们的目标，并将人类与其他动物区分开来。这项建议的总体目标是了解控制蚊子寻找宿主行为的分子事件，以便开发新的方法来减少疟疾的传播。昆虫的气味检测需要许多蛋白质成分的相互作用。其中包括气味受体和气味结合蛋白(OBP)。OBP将气味分子从嗅毛(感受器)表面输送到受体，越来越多的证据表明OBP可能直接介导某些气味受体的活动。在雌性冈比亚按蚊中，许多OBP的表达模式与寻找宿主行为的变化有关。因此，推测这些蛋白质可能与调节对人类气味的嗅觉反应有关。这项提案将通过检查这些蛋白质的结构和配体结合特性来研究这些OBP如何与人类特有的气味相互作用。这项提议将使用核磁共振(核磁共振)光谱来识别哪些气味与特定的OBP相互作用。随后，我们将确定这些复合体的三维结构，并将特定气味的结合亲和力差异与OBP和气味之间发生的特定相互作用关联起来。我们将试图回答这些问题：AgOBP是否作为对人类气味做出反应的嗅觉信号的特定调节器？配基是否诱导AgOBP的特定构象变化，这可能表明在气味受体的激活中直接起作用？一旦确定了特定AgOBP与气味分子之间相互作用的性质，这些信息将被用于指导针对OBP的新试剂的设计，目的是扰乱正常的按蚊行为，从而减少疟疾的传播。

DESCRIPTION (provided by applicant): Malaria is one of the world's most devastating diseases and is responsible for between 1-2 million deaths each year. Malaria is transmitted by the bite of a female mosquito infected with the malaria parasite. Female mosquitoes of the species Anopheles gambiae are feed almost exclusively on humans and use odors present in human sweat and skin to locate their targets and discriminate humans from other animals. The overall goal of this proposal is to understand the molecular events that control the host seeking behavior of the mosquito in order to develop new methods to reduce the transmission of malaria. Odor detection by an insect requires the interaction of a number of protein components. Among these are the Odorant Receptors and the Odorant Binding Proteins (OBPs). The OBPs transport the odor molecule from the surface of the olfactory hairs (sensilla) to the receptors and accumulating evidence suggests that OBPs may directly mediate the activity of some odorant receptors. In female A. gambiae mosquitoes, the expression patterns of a number of OBPs correlate with changes in the host-seeking behavior. Therefore, it is hypothesized that these proteins may be associated with mediating olfactory responses to human odors. This proposal will investigate how these OBPs interact with human-specific odors by examining the structure and ligand-binding properties of these proteins. This proposal will use Nuclear Magnetic Resonance (NMR) Spectroscopy to identify which odors interact with specific OBP. Subsequently we will determine the three-dimensional structure of these complexes, and correlate differences in binding affinities for particular odorants with specific interactions that occur between the OBP and the odorant. We will seek to answer the questions; do AgOBPs act as specific modulators of olfactory signaling in response to human odors? Do ligands induce specific conformational changes in the AgOBPs that could indicate a direct role in activation of odorant receptors? Once the nature of the interactions between specific AgOBPs and odor molecules are defined, this information will be used to guide the design of new reagents targeted at OBPs, with the aim of disrupting normal Anopheline mosquito behavior and so reducing the transmission of malaria.