Purified Serotonin Receptors for Structural Studies

描述(申请人提供)：5-羟色胺(5-羟色胺)是一种神经递质，与许多精神健康障碍的病因有关，包括抑郁、焦虑、社交恐惧症、精神分裂症、强迫症和恐慌症、偏头痛和饮食障碍。有12种5-羟色胺受体亚型具有相似的识别特性，但生理作用却大相径庭，属于同一家族的G蛋白偶联受体，阻碍了亚型选择性药物的发现。了解这些受体的三维结构将使选择性药物的设计成为可能。然而，由于难以纯化足够数量的同质和功能蛋白，在原子分辨率下解决膜蛋白如GPCRs的结构一直受到阻碍。在这里，我们提出了一种新颖的、专有的表达系统，结合一种纯化方法，可以获得大量高质量的纯化受体，从而解决了这些重要药物靶点的结构阐明的瓶颈。我们的目标是为12种人类5-羟色胺受体亚型中的每一种产生大量纯化的均一受体样本。这种高质量的纯化材料将是一种非常有价值的产品，使这些受体的结构得以阐明。

DESCRIPTION (provided by applicant): Serotonin (5-HT) is a neurotransmitter that has been implicated in the aetiology of numerous Mental Health disorders, including depression, anxiety, social phobia, schizophrenia, obsessive-compulsive and panic disorders, migraine, and eating disorders. There are 12 5-HT receptor subtypes with similar recognition properties yet widely divergent physiological roles that belong to the same family of G Protein Coupled Receptors (GPCRs), hindering the discovery of subtype-selective drugs. Knowledge of the 3-dimensional structure of these receptors would enable the design of selective drugs. However, solving the structure at atomic resolution of membrane proteins such as GPCRs has been hampered by the difficulty to purify sufficient amounts of homogeneous and functional protein. Here, it is proposed a novel, proprietary expression system combined with a purification method to generate large amounts of high quality purified receptor, which could solve the bottleneck for structural elucidation of these important drug targets. Our goal is to generate large amounts of purified homogenous receptor sample for each one of the 12 human 5-HT receptor subtypes. This high quality purified material will be a highly valuable product enabling structural elucidation of these receptors.