Bacterial Proteins in the Nicotinic/GABA Receptor Famil*

烟碱/GABA 受体家族中的细菌蛋白*

• 批准号: 6953613
• 负责人: GREGG B WELLS
• 金额: $ 14.55万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6953613
• 关键词: GABA receptor; Xenopus; Xenopus oocyte; bacterial proteins; biochemical evolution; electrophysiology; membrane channels; molecular biology information system; nicotinic receptors; protein purification; protein quantitation /detection; protein signal sequence; protein structure function; protein transport

DESCRIPTION (provided by applicant): Nicotinic acetylcholine receptors and GABAA receptors are members of the nicotinoid family of ligand-gated ion channel receptors of the central nervous system. They play major roles in addiction to nicotine, cocaine, alcohol, and barbiturates. Better prevention or treatment of these addictions will have major impact on human heath. High-resolution structures of these receptors are needed as a foundation on for understanding how these receptors work, how they affect addition, and how receptor-specific drugs can be designed for targeted therapeutics for addiction and also for Alzheimer's and Parkinson's diseases, epilepsy, and mental illnesses. The acetylcholine binding protein is limited as a structural model of nicotinoid receptors, because it is not an ion channel. Structures of functional nicotinoid receptors, however, have been elusive. A major obstacle has been the difficulty of obtaining enough protein, either for X-ray crystallography or with isotopic labeling for NMR. Although no bacterial nicotinoid receptors have yet been identified, such bacterial receptors could, in principle, solve this problem. Similar to the impact that bacterial potassium and chloride ion channels have on understanding those families of channels, bacterial nicotinoid receptors promise to significantly advance the understanding of the structure and function of nicotinoid receptors. We have identified several bacterial proteins whose primary amino acid sequences are similar to the extracellular domain and transmembrane domains of nicotinic acetylcholine, ionotropic GABA, and glycine receptors. The long-range goal of this project is to develop an atomic-level structural interpretation of how nicotinoid receptors contribute to addiction. The objective of this application is to determine whether bacterial proteins belong to the nicotinoid receptor family. The central hypothesis is that bacterial proteins with primary amino acid sequences that are similar to eukaryotic nicotinoid subunits are members of the nicotinoid receptor family. These specific aims test this hypothesis: (1) determine whether bacterial proteins with substantial primary sequence homology to subunits in nicotinoid family assemble into oligomers; (2) determine whether these proteins are transported to the cell surface; and (3) determine electrophysiological properties of these proteins. Identifying the first bacterial nicotinoid receptors will provide promising candidates for structural study of this important family of receptors.

描述（由申请人提供）： 烟碱乙酰胆碱受体和GABAA受体是中枢神经系统的配体门控离子通道受体的烟碱家族的成员。它们在尼古丁、可卡因、酒精和巴比妥类药物成瘾中起着重要作用。更好地预防或治疗这些成瘾将对人类健康产生重大影响。需要这些受体的高分辨率结构作为理解这些受体如何工作的基础，它们如何影响添加，以及如何设计受体特异性药物用于成瘾的靶向治疗，以及阿尔茨海默病和帕金森病，癫痫和精神疾病。乙酰胆碱结合蛋白作为烟碱受体的结构模型是有限的，因为它不是离子通道。然而，功能性烟碱受体的结构一直难以捉摸。一个主要的障碍是难以获得足够的蛋白质，无论是X射线晶体学还是核磁共振同位素标记。虽然尚未鉴定出细菌烟碱受体，但原则上，这种细菌受体可以解决这个问题。与细菌钾和氯离子通道对理解这些通道家族的影响类似，细菌烟碱受体有望显着推进对烟碱受体结构和功能的理解。我们已经确定了几种细菌蛋白的主要氨基酸序列是类似的细胞外结构域和跨膜结构域的烟碱乙酰胆碱，亲离子型GABA和甘氨酸受体。 这个项目的长期目标是开发一个原子水平的结构解释尼古丁受体如何有助于成瘾。本申请的目的是确定细菌蛋白质是否属于烟碱受体家族。核心假设是，细菌蛋白质的一级氨基酸序列与真核生物烟碱亚基相似，是烟碱受体家族的成员。这些特定的目的验证了这一假设：（1）确定与烟碱家族中的亚基具有实质性一级序列同源性的细菌蛋白质是否组装成寡聚体;（2）确定这些蛋白质是否被转运到细胞表面;以及（3）确定这些蛋白质的电生理特性。确定第一个细菌烟碱受体将提供有前途的候选人的结构研究，这一重要的受体家族。

项目成果

Synthesis and biological evaluation of 14-alkoxymorphinans. 21. Novel 4-alkoxy and 14-phenylpropoxy derivatives of the mu opioid receptor antagonist cyprodime.

14-烷氧基吗啡喃的合成和生物学评价。

• DOI: 10.1021/jm031126k
• 发表时间: 2004
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Spetea,Mariana;Schüllner,Falko;Moisa,RaduC;Berzetei-Gurske,IlonaP;Schraml,Barbara;Dörfler,Cynthia;Aceto,MarioD;Harris,LouisS;Coop,Andrew;Schmidhammer,Helmut
• 通讯作者: Schmidhammer,Helmut

Structural answers and persistent questions about how nicotinic receptors work.

关于烟碱受体如何工作的结构性答案和持续存在的问题。

• DOI: 10.2741/3094
• 发表时间: 2008
• 期刊: Frontiers in bioscience : a journal and virtual library
• 作者: Wells,GreggB

Synthesis and pharmacological activities of 6-glycine substituted 14-phenylpropoxymorphinans, a novel class of opioids with high opioid receptor affinities and antinociceptive potencies.

6-甘氨酸取代的 14-苯基丙氧基吗啡喃的合成和药理活性，一类具有高阿片受体亲和力和抗伤害作用的新型阿片类药物。

• DOI: 10.1021/jm101211p
• 发表时间: 2011
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Spetea,Mariana;Windisch,Petra;Guo,Yan;Bileviciute-Ljungar,Indre;Schütz,Johannes;Asim,MuhammadFaheem;Berzetei-Gurske,IlonaP;Riba,Pal;Kiraly,Kornel;Fürst,Susanna;Al-Khrasani,Mahmoud;Schmidhammer,Helmut
• 通讯作者: Schmidhammer,Helmut