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G蛋白偶联受体(GPCR)的研究到底有多火?

已有 23077 次阅读 2009-5-1 23:36 |个人分类:科研|系统分类:科研笔记

    世界上多个实验室在攻克GPCR结构及作用机制,原因何在? 很多药物的作用都是针对某个靶点,而在这些靶点中GPCR约占30%。因此,解析GPCR的结构不但对了解其作用机制非常关键,而且有利于设计更为有效的药物。毫不夸张,一个GPCR结构的解析对制药业来说就像是又重新注入一股新的活力。然而,目前已经解析的GPCR也只有视紫红质和肾上腺能受体两种(如下图),此外还有400多种GPCR结构没有被解析。
        
               牛视紫红质2.8埃结构(Palczewski et al,Science,2000)



                                   牛视蛋白2.9埃结构(Park et al,Nature,2008)

                        乌贼视紫红质2.5埃结构(Murakami et al,Nature,2008)

人β2肾上腺能受体3.4埃结构(Rasmussen et al,Nature,2007)

人β1肾上腺能受体2.7埃结构(Warne et al,Nature,2008)


几个有用的网站
1.GPCR与信号转导 http://www.gpcrlab.com/
2.GPCR建模 http://mosberglab.phar.umich.edu/projects/proj6.php
3. G蛋白研究网站 http://www.gproteins.com/

以下是由So Iwata教授领导的人类受体晶体学计划的简介,为期五年,准备系统地建立解析受体结构的方法学。

Mission: Establish a Methodology to Determine 3D Structure of Human GPCRs

Thanks to the Human Genome Project, many disease-causing proteins have been identified during recent years. Once 3D structure of these disease-related proteins are determined, the data can be utilized not only to develop a drug more efficiently, but also to design molecularly more targeted drug with lower side effects. Although more than 50% of commercially available drugs target membrane proteins, most notably G-protein coupled receptors (GPCRs), none of human GPCR has had its structure determined when this project started in 2006. This is mainly due to the following methodological challenges that are unique to the membrane proteins:

  • (1) They are difficult to over express and purify.
  • (2) They are difficult to crystallize because of their hydrophobicity.
  • (3) That in turn makes it difficult to obtain good X ray diffraction data.

Structure determination of human GPCR β2 adrenergic receptor by Dr. Stevens of Scripps Institute and Prof. Kobilka of Stanford in 2007 will no doubt add impetus to the structural study of human GPCR. This project aims to tackle all these challenges in order to establish a methodology for determining 3D structure of human membrane receptors systematically, capitalizing on the know-how Prof. So Iwata, the Research Director, has accumulated over the years solving structure of non-human membrane proteins. Research strategies are:

  • (1)to develop a yeast-based over expression system for functional membarne receptors, and a method to remove sacchride chains which interfere with crystallization of these proteins
  • (2) to design binders which bind to these receptors, and increase hydrophilicity and crystallizabillity
  • (3) to implement a high throughput screening system for optimization of crystallizing conditions by combining a nano-drop crystallization technique and robotic multiple-crystal-mounting system.
  • (4) to construct a low-noise data analysis system using a next generation beam line

The results of the project will have broad applications in life sciences, such as identifying various signal transduction passways in a cell, not limited in drug design.

Prof. So Iwata, the Research Director, conducts his research both in the UK and in Japan. His main research group is Membrane Protein Crystallography (MPC) Group of Imperial College London, UK. The group has another research lab at a synchrotron radiation facility Diamond where he holds the position of Diamond Fellow. Prof. Iwata currently holds positions of director of Centre for Structural Biology and David Blow Chair of Biophysics at Department of Life Sciences, Imperial College London. His another research group is Cell Biology Laboratory of Graduate School of Medicine, Kyoto University in Japan. The project is funded by ERATO (Exploratory Research for Advanced Technology), JST (Japan Science and Technology Agency), and it has research sites at Diamond in the UK and at Kyoto University in Japan. The project will enjoy cooperation with Diamond, MPC group, and Centre for Structural Biology at Imperial College London in the UK, as well as Cell Biology Laboratory at Kyoto University and Protein Research Group, RIKEN Yokohama Institute.
→more detailed info (in Japanese)



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