Structural Basis of Sigma-1 Receptor Ligand Interactions and Signalling

Sigma-1 受体配体相互作用和信号传导的结构基础

• 批准号: MR/K018590/1
• 负责人: Jason Schnell
• 金额: $ 79.67万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FK018590%2F1
• 关键词: Structural; Basis; Sigma; Receptor; Ligand

Cells have internal compartments that are specialised for unique functions including energy generation and protein production. The compartments are segregated by internal membranes that are selectively permeable. The membranes contain protein molecules ("membrane proteins") with the critical job of permitting the transfer of matter and information into and out of the intracellular compartments to enable coordination of cellular function. The Sigma-1 Receptor (S1R) is one such protein that is involved in regulating the communication between energy generating mitochondria and the endoplasmic reticulum (ER), which requires energy to produce the proteins necessary for the cell to function effectively. S1R is embedded in the ER membrane of neural cells in a region closely apposed to mitochondria and signals energy demands to the mitochondria. Because of its central role in maintaining an appropriate response to energy demands in neurons, S1R activity impacts a range of neurological conditions. S1R is regulated by both endogenous molecules and exogenous drugs, some of which are currently used therapeutically for the treatment of pain, depression, and schizophrenia. Our work aims to understand the molecular basis of S1R activity in terms of how it interacts with those drugs and how those interactions lead to communication between the ER and mitochondria. Membrane proteins like S1R that transmit signals across membranes are critical switching points in intracellular communication networks. Because of their functional importance, understanding how these proteins work is important both medically and for biotechnology and industry. As with the macroscopic world, one of the best approaches for understanding how proteins work is by observing them in detail. However, membrane proteins are extremely challenging to study by conventional methods since they must be extracted from the native cellular environment in which they have evolved to be most stable. We have developed methods to produce S1R in large quantities and purify it in large quantities from both bacterial and mammalian cells -- a necessity for robust, atomic-level observation. We propose here to take advantage of the approaches we have developed to study the structure and interactions of S1R in detail. A central technique of the proposed research is Nuclear Magnetic Resonance (NMR). NMR is a flexible, information-rich spectroscopy that provides atomic level information, and is particularly powerful in studying inter-molecular interactions in detail. We anticipate that the results of this study will (i) help to understand the mechanism of S1R in neurological disease, (ii) facilitate design of novel therapeutic agents, and (iii) facilitate structural characterisation of other membrane protein signaling proteins.

细胞具有专门用于独特功能的内部隔室，包括能量产生和蛋白质生产。隔室由选择性渗透的内膜隔离。膜含有蛋白质分子（“膜蛋白”），其关键作用是允许物质和信息转移进出细胞内区室，以协调细胞功能。Sigma-1受体（S1 R）是一种这样的蛋白质，其参与调节能量产生线粒体和内质网（ER）之间的通信，这需要能量来产生细胞有效发挥功能所必需的蛋白质。S1 R嵌入在神经细胞的ER膜中与线粒体紧密贴壁的区域中，并向线粒体发出能量需求信号。由于S1 R在维持神经元对能量需求的适当反应方面的核心作用，S1 R活性影响一系列神经系统疾病。S1 R受内源性分子和外源性药物的调节，其中一些目前用于治疗疼痛、抑郁症和精神分裂症。我们的工作旨在了解S1 R活性的分子基础，即它如何与这些药物相互作用，以及这些相互作用如何导致ER和线粒体之间的通信。像S1 R这样跨膜传递信号的膜蛋白是细胞内通讯网络的关键开关点。由于其功能的重要性，了解这些蛋白质如何工作在医学上以及生物技术和工业上都很重要。与宏观世界一样，了解蛋白质如何工作的最佳方法之一是详细观察它们。然而，通过常规方法研究膜蛋白是非常具有挑战性的，因为它们必须从它们进化为最稳定的天然细胞环境中提取。我们已经开发出大量生产S1 R并从细菌和哺乳动物细胞中大量纯化S1 R的方法-这是强大的原子级观察的必要条件。在这里，我们建议利用我们已经开发的方法来详细研究S1 R的结构和相互作用。所提出的研究的核心技术是核磁共振（NMR）。NMR是一种灵活的，信息丰富的光谱学，提供原子水平的信息，在详细研究分子间相互作用方面特别强大。我们预计，这项研究的结果将（i）有助于理解S1 R在神经系统疾病中的机制，（ii）促进新型治疗药物的设计，（iii）促进其他膜蛋白信号蛋白的结构表征。

项目成果

Re-evaluating the p7 viroporin structure.

重新评估 p7 病毒孔蛋白结构。

• DOI: 10.1038/s41586-018-0561-9
• 发表时间: 2018
• 期刊: Nature
• 影响因子: 64.8
• 作者: Oestringer BP

Solution NMR studies reveal the location of the second transmembrane domain of the human sigma-1 receptor.

• DOI: 10.1016/j.febslet.2015.01.033
• 发表时间: 2015-02-27
• 期刊: FEBS letters
• 影响因子: 3.5
• 作者: Ortega-Roldan JL;Ossa F;Amin NT;Schnell JR
• 通讯作者: Schnell JR

Characterization of the human sigma-1 receptor chaperone domain structure and binding immunoglobulin protein (BiP) interactions.

人类Sigma-1受体伴侣结构结构和结合免疫球蛋白蛋白（BIP）相互作用的表征。

• DOI: 10.1074/jbc.m113.450379
• 发表时间: 2013-07-19
• 期刊: The Journal of biological chemistry
• 作者: Ortega-Roldan JL;Ossa F;Schnell JR
• 通讯作者: Schnell JR

Perturbations of Native Membrane Protein Structure in Alkyl Phosphocholine Detergents: A Critical Assessment of NMR and Biophysical Studies.

• DOI: 10.1021/acs.chemrev.7b00570
• 发表时间: 2018-04-11
• 期刊: Chemical reviews
• 影响因子: 62.1
• 作者: Chipot C;Dehez F;Schnell JR;Zitzmann N;Pebay-Peyroula E;Catoire LJ;Miroux B;Kunji ERS;Veglia G;Cross TA;Schanda P
• 通讯作者: Schanda P