Structural Insights into TRPV Channel Gating

项目总结/摘要 瞬时受体电位（TRP）通道在人类生理学中发挥着重要作用，并促进重要的 离子（Na+、Ca ~（2+））透过质膜。本提案的重点是 受体电位香草酸亚型 2 TRPV 2在心脏功能和免疫中起重要作用， 已被列入重要的抗肿瘤药物靶点名单。尽管如此，它仍然是研究最少的TRPV 在细胞和分子水平上的通道。我们建议使用冷冻电镜， 电生理分析，定点诱变，和计算方法，以建立一个详细的 对TRPV 2通道门控机制的结构理解。在目前的提案中，我们将重点关注 了解磷酸肌醇对TRPV 2的调节，确定TRPV 2门控的机制， 配体，并剖析TRPV 2与细胞骨架相互作用的分子机制。获得的信息 在完成这些研究后，将潜在地用于TRPV 2特异性治疗剂的未来设计。

PROJECT SUMMARY/ABSTRACT Transient receptor potential (TRP) channels play significant roles in human physiology and facilitate essential ions' (Na+, Ca2+) permeation through the plasma membrane. The focus of this proposal is on the transient receptor potential vanilloid 2 (TRPV2), which plays an essential role in cardiac function and immunity, and has been placed on the list of important anti-tumor drug targets. Nevertheless, it remains the least studied TRPV channel at the cellular and molecular levels. We propose to use the combination of cryo-EM, electrophysiological analysis, site-directed mutagenesis, and computational methods to establish a detailed structural understanding of the mechanisms of TRPV2 channel gating. In this current proposal we will focus on understanding TRPV2 regulation by phosphoinositides, determine the mechanism of TRPV2 gating by diverse ligands and dissect the molecular mechanism of TRPV2 interaction with cytoskeleton. Information obtained upon completion of these studies will be potentially used for future design of TRPV2 specific therapeutics.