X-RAY STRUCTURES OF PENTAMERIC ION CHANNELS RELATED TO ANESTHETICS

麻醉相关五聚体离子通道的 X 射线结构

• 批准号: 8362142
• 负责人: AINA COHEN
• 金额: $ 0.08万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8362142
• 关键词: Anesthetics; Binding; Binding Sites; Breathing; Cations; Complex; Dose; Family; Funding; Gated Ion Channel; General Anesthesia; General anesthetic drugs; Grant; Halothane; Homologous Gene; Intravenous Anesthetics; Ion Channel; Ketamine; Ligands; Molecular; National Center for Research Resources; Principal Investigator; Proteins; Radiation; Research; Research Infrastructure; Resolution; Resources; Roentgen Rays; Source; Structure; Thiopental; United States National Institutes of Health; base; cost; novel; protein function; structural biology

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The molecular mechanism of general anesthesia remains an mystery. Although a superfamily of pentameric ligand gated ion channels (pLGICs) has been identified as potential targets of general anesthetics, the lack of high-resolution structures of these pLGICs hinders the understanding where anesthetic binding sites are in these proteins and how anesthetic bindings impact on protein functions. An exciting platform for getting the answers has recently emerged as the x-ray structures of two bacterial homologs to the pLGIC family, GLIC and ELIC, were solved. As cation channels, GLIC and ELIC can be crystallized in the open- and close-channel states, respectively. Similar to mammalian pLGIC cation channels, cation conductance of GLIC could be inhibited by a variety of anesthetics at subclinical doses. Here we propose to co-crystallize GLIC and ELIC with general anesthetics. No anesthetic has been crystallized with any pLGICs in the past. The x-ray structures of GLIC- and ELIC-anesthetics complexes will provide novel structural basis to explain the functional impact of general anesthetics to the pLGICs. Inhaled anesthetic halothane and intravenous anesthetics thiopental and ketamine are chosen for the study.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 全身麻醉的分子机制仍然是一个谜。尽管已将五聚体配件离子通道（PLGICS）的超家族确定为一般麻醉药的潜在靶标，但这些PLGIC的缺乏高分辨率结构阻碍了这些蛋白质中麻醉结合位点的理解，而这些蛋白质中是在这些蛋白质中以及麻醉对蛋白质的影响。最近出现了一个令人兴奋的答案平台，它是针对PLGIC家族的两个细菌同源物的X射线结构，即Glic和Elic。作为阳离子通道，可以在开放式和近频道状态下结晶的胶质和细胞。与哺乳动物的PLGIC阳离子通道类似，在亚临床剂量下，各种麻醉药可以抑制胶质的阳离子电导。在这里，我们建议与全身麻醉剂共结晶。过去，没有任何麻醉剂与任何PLGIC都结晶。胶质和精美 - 动作材料复合物的X射线结构将提供新的结构基础，以解释一般麻醉药对PLGICS的功能影响。吸入麻醉晕和静脉麻醉药硫代和氯胺酮用于研究。