Molecular mechanisms of sigma receptor signaling

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。

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.