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Three dimensional structure of a 12TM membrane protein

12TM膜蛋白的三维结构

基本信息

批准号：
6622864
负责人：
PHILIP L YEAGLE
金额：
$ 10.73万
依托单位：
UNIVERSITY OF CONNECTICUT STORRS
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-05-01 至 2005-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6622864
关键词：
circular dichroism membrane transport proteins nuclear magnetic resonance spectroscopy nucleic acid hybridization permease protein sequence protein structure

项目摘要

DESCRIPTION (provided by applicant): The challenge of membrane protein structure determination remains largely unmet. Thousands of water-soluble protein structures have been solved, while, in contrast, only a handful of membrane protein structures have been solved. Yet estimates suggest that 25-40 percent of the coding regions of genomes from higher organisms code for membrane proteins. As much as 60 percent of the drug targets of the pharmaceutical industry are a family of membrane proteins called G-protein coupled receptors, yet there are no X-ray crystal structures of any of these drug targets. The long-term goal of this project is to construct a path around the current problems in membrane protein structure determination through the development of a new approach to this problem. While this new approach does not replace X-ray crystallography, it does offer structural information where crystallization suitable for diffraction studies has proven impossible. It also offers the possibility of working on proteins whose size would make them unsuitable subjects for standard NMR techniques, particularly where the effective size of the membrane protein is increased by inclusion in a detergent micelle or in a lipid bicelle. In this R21 application, we focus on a difficult challenge: the solution of the structure for a 12 TM membrane protein that has so far proven refractory to X-ray crystallography. We will use what we have learned from the solution of the structures of two 7 TM membrane proteins and determine whether the same approach can be used to solve the three dimensional structure of a much larger membrane protein, the lac permease. This structure determination of the lac permease will prove very helpful in understanding the mechanism of transport for this and related proteins. Success of this project will provide a powerful new tool for proteomics that can relatively rapidly produce useful structural information for many families of membrane proteins.

描述（由申请方提供）：膜蛋白挑战结构确定在很大程度上仍未实现。上千种水溶性蛋白质结构已经解决，而相比之下，只有少数膜蛋白结构已被解决。然而，据估计，25-40 来自高等生物的基因组编码区的百分比为膜蛋白多达60%的药物靶点在制药工业中，有一类膜蛋白，称为G蛋白偶联受体，但没有X射线晶体结构的任何这些药物靶点该项目的长期目标是建造一条道路，目前膜蛋白结构测定中存在的问题，为解决这一问题提出了一种新的方法。虽然这种新方法不取代了X射线晶体学，它确实提供了结构信息，已经证明不可能进行适合于衍射研究的结晶。它还提供了研究蛋白质的可能性，不适合标准NMR技术的对象，特别是在膜蛋白的有效大小通过包含在去污剂中而增加胶束或脂质胶束中。在这个R21应用程序中，我们专注于一个困难的挑战：解决12 TM膜蛋白的结构，迄今为止被证明对X射线晶体学是无效的。我们会用我们所拥有的从两个7 TM膜蛋白的结构的解决方案中了解到，确定是否可以使用相同的方法来解决三维一个更大的膜蛋白，紫胶通透酶的结构。这种结构紫胶通透酶的测定将证明非常有助于了解这是它和相关蛋白质的运输机制。这个项目成功将为蛋白质组学提供一个强大的新工具，为许多膜蛋白家族提供有用的结构信息。