INTERLEUKIN-2 (IL-2)

白细胞介素-2 (IL-2)

• 批准号: 8363360
• 负责人: Karen A Allen
• 金额: $ 0.77万
• 依托单位: BROOKHAVEN SCIENCE ASSOC-BROOKHAVEN LAB
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8363360
• 关键词: Amino Acids; Binding; Binding Sites; Biochemical; Biological Assay; Computing Methodologies; Crystallography; Funding; Grant; Hot Spot; Interleukin-2; Light; Measures; Molecular; National Center for Research Resources; Principal Investigator; Proteins; Research; Research Infrastructure; Resources; Site; Source; Synchrotrons; United States National Institutes of Health; X-Ray Crystallography; cost; cytokine; inhibitor/antagonist; receptor; small molecule

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. Inhibition of the interaction between Interleukin-2 (IL-2), an immunoregulatory cytokine, and its receptor alpha chain (IL-2R alpha) using small molecules is an extensively studied problem, and there exist two examples of small molecular inhibitors of IL-2, both of which have been characterized by X-ray crystallography. Both inhibitors bind at the same site on IL-2, which coincides with the binding interface to IL-2R alpha and involves interactions with some of the amino acid residues on IL-2 known to comprise the energetic hot spot for IL-2/IL-2R alpha binding. It was shown that the small molecule binding site can be divided into two subsites, the first being a largely polar and rigid pocket, the second a highly adaptive hydrophobic region. The binding energies that different portions of the known inhibitors derive from their interactions with the protein have not been systematically elucidated. We will measure experimental binding energies and binding orientations for different molecular fragments derived from these known IL-2 inhibitors, using quantitative biochemical and biophysical assays as well as X-ray crystallography, and will compare the results with those obtained computationally using the same fragments as probes. The results will provide new information on the physicochemical and structural features that render a difficult PPI site druggable, which we will use to further refine our computational method.

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。 使用小分子抑制白细胞介素-2（IL-2）（一种免疫调节细胞因子）与其受体α链（IL-2 R α）之间的相互作用是一个广泛研究的问题，并且存在IL-2的小分子抑制剂的两个实例，这两个实例都已通过X射线晶体学表征。两种抑制剂结合在IL-2上的相同位点，该位点与IL-2 R α的结合界面一致，并涉及与IL-2上的一些氨基酸残基的相互作用，这些氨基酸残基已知包含IL-2/IL-2 R α结合的能量热点。结果表明，小分子结合位点可以分为两个亚位点，第一个是一个很大的极性和刚性口袋，第二个是一个高度适应性的疏水区域。 已知抑制剂的不同部分从它们与蛋白质的相互作用中获得的结合能尚未被系统地阐明。我们将使用定量生物化学和生物物理分析以及X射线晶体学测量来自这些已知IL-2抑制剂的不同分子片段的实验结合能和结合方向，并将结果与使用相同片段作为探针计算获得的结果进行比较。这些结果将提供有关使PPI位点难以药物化的物理化学和结构特征的新信息，我们将使用这些信息来进一步完善我们的计算方法。