SATBILIZATION OF ALPHA4, BETA2, ALPHA7 NACHRS USING COMPUTATIONAL METHODS

使用计算方法稳定 ALPHA4、BETA2、ALPHA7 NACHRS

• 批准号: 8364301
• 负责人: JEFFRY D. MADURA
• 金额: $ 0.11万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8364301
• 关键词: Acetylcholine; Affect; Anesthetics; Binding; Biomedical Research; Cells; Cellular Membrane; Cholinergic Receptors; Computing Methodologies; Funding; Gated Ion Channel; General anesthetic drugs; Glycine Receptors; Goals; Grant; High Performance Computing; Ion Channel Gating; Lipids; Membrane; Membrane Proteins; Muscle; Mutation; National Center for Research Resources; Nervous system structure; Neuraxis; Neurons; Neurotransmitters; Nicotinic Receptors; Nuclear Magnetic Resonance; Play; Principal Investigator; Process; Protein Subunits; Proteins; Research; Research Infrastructure; Resolution; Resources; Role; Site; Source; Structure; Transmembrane Domain; United States National Institutes of Health; cost; receptor; response; simulation

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 central nervous system is responsible for coordinating the various processes of the body. Acetylcholine plays an important role in the central nervous system as a neurotransmitter that elicits a variety of cellular responses. The main activity of the acetylcholine neurotransmitter is the excitation of muscle tissue. Acetylcholine interacts with its target cells by binding to acetylcholine receptors in cellular membranes. Nicotinic acetylcholine receptors (nAChRs) are an example of membrane-bound acetylcholine receptor proteins. These receptors are also putative targets of interaction with anesthetic drugs. Most study of the interaction between receptor proteins and anesthetic drugs is technically challenging due to the difficulty of isolating membrane proteins and limitations when using nuclear magnetic resonance (NMR) to elucidate receptor structure at a high resolution. Within the membrane, both neurotransmitter ion-gated channels and cys-loop regions of membranous proteins have been implicated as sites of interaction with general anesthetics. Studies have thus far demonstrated that nAChRs are composed of various protein subunits which span the membrane and extend extracellularly while the pore of the receptor is located inside the membrane with a surrounding frame that separates it from the lipids within the membrane. Neuronal nAChRs can be composed of different subunits, such as a heteromeric nAChR of two a4 and three b2 subunits, or a homomeric nAChR containing five a7 subunits. Our ultimate goal is to gain an understanding of the mechanism by which anesthetic drugs affect the nervous system. In order to reach this goal, computational methods will be used in an attempt to find mutations of the b2 and a7 neuronal nAChRs and the a1 glycine receptor that are more stable at a lower pH. Computational methods of simulation and structural determination will be used in an effort to stabilize the a4, b2, and a7 proteins of the transmembrane domain of the nAChRs. The a1 glycine receptor will also be studied similarly.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 中枢神经系统负责协调身体的各种过程。乙酰胆碱作为一种神经递质在中枢神经系统中起着重要作用，它能激发多种细胞反应。乙酰胆碱神经递质的主要活动是兴奋肌肉组织。乙酰胆碱通过与细胞膜上的乙酰胆碱受体结合而与靶细胞相互作用。烟碱型乙酰胆碱受体（nAChR）是膜结合乙酰胆碱受体蛋白的一个实例。这些受体也是与麻醉药物相互作用的假定靶点。大多数受体蛋白和麻醉药物之间的相互作用的研究是技术上具有挑战性的，由于分离膜蛋白的困难和限制时，使用核磁共振（NMR），以阐明受体结构在高分辨率。在膜内，神经递质离子门控通道和膜蛋白的cys环区域都被认为是与全身麻醉剂相互作用的位点。迄今为止的研究表明，nAChR由跨越膜并在细胞外延伸的各种蛋白质亚基组成，而受体的孔位于膜内，周围的框架将其与膜内的脂质分开。神经元nAChR可以由不同的亚基组成，如两个α 4和三个β 2亚基的异聚nAChR，或含有五个α 7亚基的同源nAChR。我们的最终目标是了解麻醉药物影响神经系统的机制。为了达到这一目标，将使用计算方法，试图找到突变的b2和a7神经元nAChRs和a1甘氨酸受体，在较低的pH值更稳定。计算方法的模拟和结构的确定将被用于努力稳定的a4，b2，和a7蛋白的跨膜结构域的nAChRs。也将类似地研究α 1甘氨酸受体。