STRUCTURAL STUDIES OF G-PROTEIN COUPLED RECEPTORS DIMERS USING DISCRETE REPRESE

使用 Discrete Represe 对 G 蛋白偶联受体二聚体进行结构研究

• 批准号: 7601344
• 负责人: Marta Filizola
• 金额: $ 0.03万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7601344
• 关键词: Atomic Force Microscopy; Cells; Choline; Computer Retrieval of Information on Scientific Projects Database; Dimerization; Environment; Family; Funding; G-Protein-Coupled Receptors; Goals; Grant; Helix (Snails); Homology Modeling; Institution; Lipid Bilayers; Maps; Membrane; Molecular; Mus; Pliability; Property; Proteins; Range; Relaxation; Research; Research Personnel; Resources; Rhodopsin; Source; System; United States National Institutes of Health; base; dimer; ear helix; molecular dynamics; molecular modeling; monomer; nanosecond; receptor coupling; research study; simulation; two-dimensional

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. Exploration of the structural features of G-protein coupled receptor (GPCR) dimerization/oligomerization is at its very beginning. Both computation and experiment seek to reveal the basis of protein interactions in GPCR dimers, and the dynamic properties that may relate to the functional mechanisms. Inferences from a recent atomic-force microscopy map of rhodopsin molecules in their native mouse disk membranes (Liang et al., J. Biol. Chem. 2003, 278:21655-21662) suggest that rhodopsin is organized into two-dimensional arrays of dimers, with the transmembrane (TM) helices 4 and 5 involved in intradimeric contact. Our plan is to carry out a detailed molecular dynamics (MD) simulation of the recently proposed molecular model of the TM4,5-TM4,5 rhodopsin dimer within a large unit cell (a=160 ¿ b= 124 ¿ and c= 98 ¿) of a hydrated patch of palmitoyl-oleoyl-phosphatidyl choline (POPC) lipid bilayer membrane containing 20 ¿ 16 ¿ 2 POPC molecules. Results from this simulation will be compared with those from parallel calculations performed on the rhodopsin monomer with the goal of identifying domains of high flexibility in the nanosecond range that may be functionally important with regard to oligomerization. The inferences concerning structural relaxation of the dimeric system within a meaningful explicit representation of the molecular membrane environment are generalizable to other GPCRs in the same family, for which only homology models are available.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 对G蛋白偶联受体（GPCR）二聚/寡聚化结构特征的探索才刚刚开始。计算和实验都试图揭示GPCR二聚体中蛋白质相互作用的基础，以及可能与功能机制相关的动力学性质。从最近的天然小鼠盘膜中的视紫红质分子的原子力显微镜图的推断（Liang等人，J.Biol.Chem.2003，278：21655-21662）表明视紫红质被组织成二聚体的二维阵列，其中跨膜（TM）螺旋4和5参与二聚体内接触。我们的计划是进行详细的分子动力学（MD）模拟最近提出的分子模型的TM 4，5-TM 4，5视紫红质二聚体在一个大的单位细胞（a=160 B= 124和c= 98）的水合补丁的棕榈酰-油酰-磷脂酰胆碱（POPC）脂质双层膜含有20 16 2 POPC分子。从这个模拟的结果将进行比较与那些从并行计算进行的视紫红质单体的目标是确定域的高灵活性在纳秒范围内，可能是功能上重要的寡聚化。关于分子膜环境的有意义的明确表示内的二聚体系统的结构弛豫的推论可推广到同一家族中的其他GPCR，对于这些GPCR，仅同源模型可用。