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Molecular mechanisms of sigma receptor signaling

西格玛受体信号传导的分子机制

基本信息

批准号：
9906922
负责人：
Andrew Kruse
金额：
$ 32.47万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-15 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9906922
关键词：
Address Agonist Amyotrophic Lateral Sclerosis Animals Binding Biochemical Cells Classification Collaborations Communication Complement Computer Simulation Computing Methodologies Crystallization Crystallography Data Disease Dissociation Electron Microscopy Engineering Fluorescence G Protein-Coupled Receptor Signaling Health Heart failure High Density Lipoproteins Human Human Genome Immunoglobulin Fragments Investigation Ion Channel Lead Ligand Binding Ligands Manuscripts Mass Spectrum Analysis Measures Mediating Membrane Lipids Methods Molecular Molecular Conformation NMR Spectroscopy Neurodegenerative Disorders Pharmaceutical Preparations Pharmacology Physiological Physiology Primary Lateral Sclerosis Process Property Proteins Proteomics Protomer Receptor Activation Receptor Signaling Regulation Resolution Role Signal Transduction Structure Techniques Testing Therapeutic Work X-Ray Crystallography experimental study flexibility human disease insight nanodisk neglect novel radioligand receptor receptor function reconstitution response sigma receptors sigma-1 receptor single molecule tool

项目摘要

Abstract The sigma-1 receptor is an enigmatic transmembrane receptor in humans that has been implicated in a variety of disease processes, including neurodegenerative disease and heart failure. Recently, the sigma receptor has been identified as a regulator of ion channel and GPCR signaling. Despite the growing recognition of the importance of this protein, very little is known regarding the molecular basis for its activity or its contribution to disease. We will study the sigma receptor using a multifaceted approach to examine structure, pharmacology, and dynamics of this important protein. Initial efforts will focus on the use of X-ray crystallography to probe receptor activation mechanism using conformationally selective antibody fragments. Complementing this work, we will explore the role of oligomerization in sigma receptor function using electron microscopy and other methods, and we will characterize the structural dynamics of the receptor by NMR spectroscopy and computational simulations. In the long term, we aim to establish a detailed molecular understanding of the sigma receptor activity and its role in human health and disease.

摘要 sigma-1受体是人类中一种神秘的跨膜受体，其与多种包括神经退行性疾病和心力衰竭。最近，sigma受体被鉴定为离子通道和GPCR信号转导的调节剂。尽管人们越来越认识到虽然这种蛋白质的重要性，但关于其活性的分子基础或其对疾病我们将使用多方面的方法研究sigma受体，以检查结构，药理学，和这种重要蛋白质的动力学。最初的努力将集中在使用X射线晶体学来探测使用构象选择性抗体片段的受体活化机制。作为这项工作的补充，我们将使用电子显微镜和其他方法来探索寡聚化在sigma受体功能中的作用。方法，我们将通过NMR光谱表征受体的结构动力学，计算机模拟从长远来看，我们的目标是建立一个详细的分子理解， σ受体活性及其在人类健康和疾病中作用。