Understanding of G protein-coupled odorant receptors function

翻译后摘要：我们的大脑使用的策略来检测和理解其不稳定的环境是嗅觉。 嗅觉感知开始于气味与嗅觉细胞表达的气味受体（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 由一组气味剂激活，并且一种气味剂可以激活OR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，一种气味 给定的浓度可以通过OR的激活模式来描述，这对每种气味都是特异性的。在这 在感官上，破解大脑用来感知气味的机制需要理解气味-或 交互.在G蛋白偶联受体家族（GPCR）中，视紫红质类包含亚家族 与气味感知相关的器官GPCR在药理学中是必不可少的，因为它们代表了三分之一 的药物靶点。它们的结构决定，如β 2肾上腺素能受体， 了解药物如何与其靶点相互作用。尽管OR代表了GPCR家族的近一半 在人类中有400个不同的成员，没有一个在结构上被阐明，特别是由于它们的挑战性， 在细胞系统中表达。通过与非嗅觉GPCR的同源性构建的OR的理论结构是 目前最先进的技术，以获得关于OR功能的基础知识。这种模式将大大受益于 OR结构模板。利用手术室的多样性，我将设计新的气味受体， “共识OR”。它们的表达以及激活和抑制机制将与 结构阐明的非嗅觉GPCR。因此，我将获得一组性能良好的OR， to in silico硅片and in vitro体外approaches方法.这种跨学科的研究策略将包括分子建模， 功能测定、定点诱变、蛋白质生产和纯化。至关重要的是， 确定管理OR和GPCR功能的一般机制。它将允许描述 气味或互动与前所未有的细节水平，以及了解我们的大脑的策略， 用来感知嗅觉环境

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.