Understanding of G protein-coupled odorant receptors function

摘要：我们的大脑用嗅觉来检测和理解其不稳定的环境。 嗅觉始于气味与嗅觉表达的气味受体(OR)的相互作用 感觉神经元(OSN)气味识别遵循组合编码方案，其中一个OR可以是 被一组气味物质和一种气味物质激活可以激活ORs的组合。通过这样的组合 通过编码，生物体可以检测和区分无数的挥发性气味分子。因此，空气中的气味 给定的浓度可以用ORs的激活模式来描述，该模式对每种气味都是特定的。在那 感官，破解大脑感知气味的机制需要理解气味-或 互动。在G蛋白偶联受体家族中，视紫红质类包含亚家族 与气味感知相关的ORS。GPCR在药理学中是必不可少的，因为它们代表着三分之一 毒品目标的。它们的结构测定，如β2肾上腺素能受体，对此有帮助。 了解药物如何与其靶标相互作用。尽管OR代表了GPCR大家庭的近一半 人类有400个不同的成员，没有一个在结构上被阐明，特别是因为他们的挑战性 在细胞系统中的表达。通过与非嗅觉GPCR同源建立的ORs的理论结构是 目前最先进的或函数的基本知识。这样的模式将大大受益于 OR结构模板。利用OR曲目的多样性，我将设计一种新的气味感受器，称为 “共识OR”。它们的表达和激活和抑制机制将可与 从结构上阐明了非嗅觉GPCR。因此，我将获得一组表演者的OR，它将受到 在硅胶和体外方法中。这一跨学科研究战略将包括分子建模， 功能分析、定点突变、蛋白质生产和纯化。它对以下方面至关重要 确定管理组织职能的一般机制和一般的GPCRs。它将允许描述 气味-或以前所未有的细节进行交互，以及理解我们大脑的策略 用来感知它的嗅觉环境。

Abstract: The strategy used by our brain to detect and make sense of its volatile environment is olfaction. Olfactory perception begins with the interaction of odorants with odorant receptors (OR) expressed by olfactory sensory neurons (OSN). Odor recognition follows a combinatorial coding scheme, where one OR can be activated by a set of odorants and one odorant can activate a combination of ORs. Through such combinatorial coding, organisms can detect and discriminate between a myriad of volatile odor molecules. Thus, an odor at a given concentration can be described by an activation pattern of ORs, which is specific to each odor. In that sense, cracking the mechanisms that the brain uses to perceive odor requires the understanding odorant-OR interactions. In the G protein coupled receptor family (GPCR), the rhodopsin class contains the subfamily associated with odor perception, the ORs. GPCRs are essential in pharmacology since they represent a third of the drug target. Their structural determination, such as for the beta 2 adrenergic receptor, has helped understanding how drugs interact with their target. Despite ORs represent nearly a half of the GPCR family with 400 different members in humans, none has been structurally elucidated, notably due to their challenging expression in cell systems. Theoretical structures of ORs built by homology with non-olfactory GPCRs are currently state-of-the-art to gain fundamental knowledge on OR function. Such models will strongly benefit from an OR structure template. Using the diversity of the OR repertoire, I will design new odorant receptors called "consensus ORs". Their expression and mechanisms of activation and inhibition will be comparable to structurally elucidated non-olfactory GPCR. I will thus obtain a performant set of ORs, which will be subjected to in silico and in vitro approaches. This transdisciplinary research strategy will include molecular modeling, functional assays, site-directed mutagenesis, protein production and purification. It is of central importance to identify general mechanisms governing the function of ORs and GPCRs in general. It will allow describing odorant-OR interaction with unprecedented level of details, as well as understanding the strategy our brain uses to perceive its olfactory environment.