Allosteric modulation of EAG1 gating

EAG1 门控的变构调节

基本信息

批准号：
8551787
负责人：
Gail A Robertson
金额：
$ 28.74万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-30 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8551787
关键词：
Address Adopted Alanine Amino Acids Behavior Binding Biochemical Biological Assay Brain Calorimetry Cancerous Cells Chemical Modifier Chemicals Complex Coupling Cyclic AMP-Dependent Protein Kinases Cyclic Nucleotides Cysteine Data Enzymes Exhibits Family Family member Fluorescent Probes Fluorometry In Vitro Investigation Ion Channel Knowledge Laboratories Lead Ligands Link Malignant Neoplasms Mediating Methodology Modeling Molecular Conformation Monitor Movement Mutagenesis N-terminal Neuraxis Outcome Pharmaceutical Preparations Physiological Proteins Reagent Regulation Reporting Roentgen Rays Role Side Structure Surface Plasmon Resonance System Testing Therapeutic Voltage-Gated Potassium Channel Work Xenopus oocyte chemotherapy cyclic-nucleotide gated ion channels deletion analysis drug development in vitro testing loss of function molecular marker mutant novel research study screening sensor therapeutic development tool voltage voltage clamp

项目摘要

DESCRIPTION (provided by applicant): Eag-related channels (EAG, hERG, ELK) all share a highly conserved region bearing homology with cyclic- nucleotide binding domains of a variety of other proteins including cyclic nucleotide-gated channels. However, most evidence indicates this domain has evolved to serve a different, but unknown, function in Eag-related channels. This application introduces a new X-ray crystal structure for the EAG1 cyclic nucleotide homology domain (CNBhD) and proposes experiments directed by structural considerations to probe its function as an allosteric modulator of channel gating. Molecules interacting with this domain and modifying channel behavior will be identified through a layered screening approach. A range of biochemical and functional approaches reflecting complementary strengths of the participating laboratories will be employed. This project is expected to address a long-standing question in the field regarding the structure and function of CNBhD's, and produce reagents that will ultimately help define the functional role of EAG1 channels in the brain and facilitate chemotherapeutic drug development.

描述（由申请人提供）：EAG相关的通道（EAG，HERG，ELK）均与高度保守的区域具有同源性，该区域与循环 - 核苷酸结合结构域具有多种其他蛋白质，包括环状核苷酸门控通道。但是，大多数证据表明该领域已经演变为在与EAG相关的通道中的功能不同但未知的功能。该应用引入了一种新的X射线晶体结构，用于EAG1环状核苷酸同源性域（CNBHD），并提出了通过结构考虑的实验，以探测其作为通道门控的变构调节剂的功能。与该域相互作用并修改通道行为的分子将通过分层筛选方法识别。将采用一系列反映参与实验室互补优势的生化和功能方法。预计该项目将解决有关CNBHD的结构和功能的一个长期问题，并生产试剂，最终将有助于确定EAG1通道在大脑中的功能作用并促进化学治疗药物的开发。