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.

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。 中枢神经系统负责协调身体的各个过程。乙酰胆碱在中枢神经系统中起着重要作用，作为神经递质，引起了多种细胞反应。乙酰胆碱神经递质的主要活性是肌肉组织的激发。乙酰胆碱通过与细胞膜中的乙酰胆碱受体结合而与其靶细胞相互作用。烟碱乙酰胆碱受体（NACHR）是膜结合的乙酰胆碱受体蛋白的一个例子。这些受体也是与麻醉药物相互作用的假定靶标。大多数研究受体蛋白与麻醉药之间的相互作用在技术上具有挑战性，这是由于难以分离膜蛋白和使用核磁共振（NMR）以高分辨率阐明受体结构时的局限性。在膜内，膜蛋白的神经递质离子门控通道和CYS环区域都被认为是与全身麻醉剂相互作用的部位。到目前为止，研究表明，NACHR由各种蛋白质亚基组成，这些蛋白质亚基跨越膜并细胞外延伸，而受体的孔位于膜内，其周围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，例如两个A4和三个B2亚基的异质NACHR，或包含五个A7亚基的同源性NACHR。我们的最终目标是了解麻醉药物影响神经系统的机制。为了实现此目标，将使用计算方法来寻找B2和A7神经元NACHR和A1甘氨酸受体的突变，它们在较低的pH下更稳定。将使用模拟和结构测定的计算方法，以稳定NACHRS的跨膜结构域的A4，B2和A7蛋白。 A1甘氨酸受体也将类似地研究。