THREE DIMENSIONAL MODELS FOR MEMBRANE RECEPTOR PROTEINS

膜受体蛋白的三维模型

基本信息

批准号：
6330479
负责人：
TERRY P LYBRAND
金额：
$ 13.9万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1995
资助国家：
美国
起止时间：
1995-06-01 至 2004-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6330479
关键词：
G protein adrenergic receptor affinity labeling biological signal transduction chemical models chemoreceptors chemotaxis cholecystokinin computer simulation dopamine receptor hormone receptor ligands protein structure function receptor binding site directed mutagenesis structural biology

项目摘要

Integral membrane receptor proteins often play a key role in signal transduction across cell membranes in both bacteria and higher organisms. Detailed knowledge of the three-dimensional structures of these receptor proteins would undoubtedly contribute greatly to a general understanding of the molecular mechanisms of signal transduction, but formidable technical challenges prohibit the routine determination of high resolution structures for most membrane proteins at present. Therefore, computer modeling studies are proposed to generate detailed three-dimensional models for a bacterial membrane chemoreceptor, the Trg receptor from Escherichia coli, and a number of mammalian seven helix G protein-coupled receptors, including adrenergic and dopamine neurotransmitter receptors, and CCK-A peptide receptor. Several specific issues of adrenergic and dopamine receptor ligand binding and selectivity will be addressed utilizing molecular modeling techniques and existing experimental data. Molecular modeling studies and photoaffinity labeling experiments will be performed for CCK-A receptor, in collaboration with Prof. Laurence Miller at Mayo Clinic, to fully characterize agonist and antagonist binding sites. A final set of modeling studies will be undertaken in collaboration with Prof. Gerald Hazelbauer at Washington State University to generate detailed three-dimensional models for the bacterial Trg chemoreceptor. Utilizing data from sulfhydryl accessibility, crosslinking, and spin labeling studies performed by Prof. Hazelbauer's group, structures for the transmembrane and periplasmic domains of the receptor will be constructed, and models for the conformational changes associated with signal transduction will be explored. The model structures will be continually evaluated and refined using new experimental data from Prof. Hazelbauer's laboratory. The combination of detailed model building and close collaboration with experimental groups should yield useful new information about structure and signal transduction mechanisms for two distinct classes of membrane receptor proteins. Information obtained for the adrenergic, dopamine, and CCK-A receptors may also be of use in design of pharmacological agents targeted to these receptors.

整合膜受体蛋白通常在信号传导中发挥关键作用在细菌和高等动物中跨细胞膜转导有机体。详细了解三维结构这些受体蛋白无疑将极大地促进对信号分子机制的一般理解转导，但巨大的技术挑战阻碍了常规确定大多数膜蛋白的高分辨率结构现在。因此，建议进行计算机建模研究生成细菌膜的详细三维模型化学感受器、大肠杆菌的 Trg 受体以及许多哺乳动物七螺旋 G 蛋白偶联受体，包括肾上腺素能受体多巴胺神经递质受体和 CCK-A 肽受体。肾上腺素能和多巴胺受体配体的几个具体问题将利用分子模型解决结合和选择性问题技术和现有的实验数据。分子模型研究并对CCK-A进行光亲和标记实验受体，与梅奥诊所的劳伦斯·米勒教授合作，充分表征激动剂和拮抗剂结合位点。最后一组模型研究将与教授合作进行。华盛顿州立大学的 Gerald Hazelbauer 将生成详细的细菌 Trg 化学感受器的三维模型。利用来自巯基可及性、交联和自旋标记的数据 Hazelbauer 教授小组进行的研究，结构受体的跨膜和周质结构域将是构建了与相关的构象变化模型将探讨信号转导。模型结构将是使用教授的新实验数据不断评估和完善。哈泽尔鲍尔的实验室。详细模型构建和与实验小组的密切合作应该会产生有用的新成果有关两种物质的结构和信号转导机制的信息不同类别的膜受体蛋白。获得的信息用于肾上腺素能受体、多巴胺受体和 CCK-A 受体也可用于针对这些受体的药物制剂的设计。