INTEGRAL MEMBRANE PROTEIN FATTY ACID AMIDE HYDROLASE: STRUCTURE AND FUNCTION

完整膜蛋白脂肪酸酰胺水解酶：结构和功能

• 批准号: 7721772
• 负责人: MICHAEL H BRACEY
• 金额: $ 0.02万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7721772
• 关键词: Amides; Body Temperature; CNR1 gene; Cannabinoids; Class; Cognitive; Complex; Computer Retrieval of Information on Scientific Projects Database; Desire for food; Development; Drug usage; Enzymes; Fatty Acids; Funding; Generations; Grant; Institution; Integral Membrane Protein; Knowledge; Learning; Link; Memory; Molecular Target; Nervous System Physiology; Orthologous Gene; Pain Threshold; Physiology; Process; Regulation; Research; Research Personnel; Resolution; Resources; Sleep; Source; Structure; System; Therapeutic; United States National Institutes of Health; Variant; design; fatty acid amide hydrolase; in vivo; inhibitor/antagonist; member; mutant; three dimensional structure

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The mammalian fatty acid amides (FAAs) have been directly linked to the regulation of pain thresholds, body temperature, sleep cycles, appetite, and higher-level cognitive processes such as memory and learning. Nonetheless, how FAAs influence nervous system function is poorly understood. While some of these molecules trigger the central cannabinoid receptor CB1, other members of this class lack described molecular targets. The enzyme fatty acid amide hydrolase (FAAH) controls the levels of fatty acid amides in vivo, setting the baseline function of their various corresponding physiologies. We have recently determined the three dimensional structure of this integral membrane protein to 2.8 ¿, and we are now prepared to begin second-generation structure determination efforts to extend our knowledge of the mechanisms of action of this important enzyme. The studies described in this application aim to determine higher resolution FAAH structures, as well as structures of FAAH orthologs, apo-FAAH, FAAH-inhibitor/product complexes, and key FAAH mutants, including the natural P129T variant associated with problem drug use. Information accrued from our studies will not only enlighten our understanding of FAAH but will also serve as a guide for the development of agents designed to intersect the cannabinoid and other FAA systems in vivo, possibly to therapeutic benefit.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 哺乳动物脂肪酸酰胺(FAAs)与痛阈值、体温、睡眠周期、食欲以及记忆和学习等高级认知过程的调节直接相关。尽管如此，FAAs如何影响神经系统功能还知之甚少。虽然其中一些分子触发中央大麻素受体CB1，但这类分子中的其他成员缺乏所描述的分子靶点。脂肪酸酰胺水解酶(FAAH)控制体内脂肪酸酰胺的水平，设定其各种相应生理功能的基线。我们最近已经确定了这种完整的膜蛋白的三维结构为2.8°，现在我们准备开始第二代结构测定工作，以扩展我们对这种重要酶的作用机制的了解。本申请中描述的研究旨在确定更高分辨率的FAAH结构，以及FAAH同系物、apo-FAAH、FAAH抑制剂/产物复合体和关键FAAH突变体的结构，包括与问题药物使用相关的天然P129T突变体。从我们的研究中获得的信息不仅将启发我们对FAAH的理解，而且还将作为开发旨在使大麻素和其他FAA系统在体内相交的药物的指南，可能有助于治疗。