Threading transmembrane protein structures: G protein-coupled receptor case study

本研究的目的是开发和验证准确预测全长螺旋跨膜蛋白的线索框架，然后将这些算法应用于预测人G蛋白偶联受体(GPCR)蛋白及其剪接变异体的结构。 跨膜蛋白是人类生物学功能的重要方面，它们在呼吸、信号转导、细胞转运以及化合物和离子的跨细胞膜运输等细胞过程中起着至关重要的作用。一些跨膜蛋白功能障碍与阿尔茨海默氏症和糖尿病等疾病有关[1，2]。它们也是超过50%的制药药物的靶标。为了更好地了解它们的功能机制，进而帮助更好地了解它们相关疾病的机制，必须确定三维(3D)结构。这项研究试图通过一种称为线索的技术，以GPCR为例，为预测膜蛋白的3D结构提供线索框架。线程是指将查询序列与所有有代表性的结构进行能量比对。 为了实现上述目标，将开发一个基于线程的框架来预测α螺旋跨膜蛋白的主干结构，然后利用现有的结构精化工具来获得全原子结构。接下来，在第一步和第二步中获得和提炼的线状框架将应用于约701个人视紫质GPCR及其剪接变异体。

The purpose of this proposed study is to develop and validate threading framework for accurately predicting full-length helical trans-membrane proteins; then apply these algorithms to predict the structures of human G- protein coupled receptor (GPCR) proteins and their spliced variants. Trans-membrane proteins are very important aspect of human biological function, they serve critical roles in cellular processes such as respiration, signal transduction, cell trafficking, and transport of compounds and ions across cellular membranes. Dysfunctions in some trans-membrane proteins have been associated with diseases such as Alzheimer's and diabetes [1, 2]. They are also a target for more than 50% of pharmaceutical drugs. To better understand the mechanism of their function, which in turn help better understand the mechanism of their associated diseases, the three dimensional (3D) structure must be determined. This research seeks to provide a threading framework for predict the 3D structure of membrane proteins, using GPCR as case study, through the technique called threading. Threading is when a query sequence is aligned to all representative structures energetically. To achieve the above aims, a threading-based framework for predicting the backbone structures of alpha helical trans-membrane proteins will be developed, then adapt exiting structural refinement tools to obtain full- atom structures. Next, the threading framework obtained and refined in step one and two will be applied to the about 701 human rhodopsin GPCR and its spliced variants.