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Structural Insights into TRPV Channel Gating

TRPV 通道选通的结构见解

基本信息

批准号：
10022499
负责人：
Vera Moiseenkova-Bell
金额：
$ 44.6万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10022499
关键词：
Actins Address Agonist Applications Grants Axon Binding Binding Sites Biology Borates Brain Cannabidiol Cardiac Cell Line Cell Proliferation Cell membrane Complex Computing Methodologies Cryoelectron Microscopy Cytoskeleton Data Development Drug Targeting Electrophysiology (science)Event Family Family member Funding Future Grant Homeostasis Human Human body Immunity Intracellular Membranes Ions Laboratories Length Ligand Binding Ligands Lipid Binding Lipids Membrane Membrane Lipids Molecular Molecular Conformation Mus Neurons Phosphatidylinositols Physiological Physiology Play Probenecid Process Proteins Recommendation Regulation Reporting Research Resolution Rest Role Sensory Site-Directed Mutagenesis Stretching Structure TRP channel TRPV channel Therapeutic Time Tranilast Tubulin United States National Institutes of Health Vanilloid antitumor drug base beta Tubulin cancer cell desensitization design heart function insight instrumentation member nanodisk novel programs protein protein interaction receptor structured lipid

项目摘要

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.

项目总结/摘要瞬时受体电位（TRP）通道在人体生理学中起着重要作用，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。