Allosteric modulation of EAG1 gating

描述(申请人提供)：EAG相关的通道(EAG，HERG，ELK)都有一个高度保守的区域，与包括环核苷酸门控通道在内的各种其他蛋白质的环核苷酸结合结构域同源。然而，大多数证据表明，这个区域已经进化为在EAG相关渠道中服务于不同的、但未知的功能。本申请介绍了一种新的EAG1环核苷酸同源结构域(CNBhD)的X射线晶体结构，并提出了基于结构考虑的实验，以探索其作为通道门控变构调制器的功能。与该结构域相互作用并改变通道行为的分子将通过分层筛选方法进行识别。将采用一系列反映参与实验室优势互补的生化和功能方法。该项目有望解决该领域中关于CNBhD结构和功能的长期问题，并生产最终将有助于确定EAG1通道在大脑中的功能作用并促进化疗药物开发的试剂。

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.