INTERLEUKIN-2 (IL-2)

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 用小分子抑制免疫调节细胞因子白介素2(IL-2)与其受体α链(IL-2Rα)之间的相互作用是一个被广泛研究的问题，有两个小分子的IL-2抑制剂的例子，这两个例子都经过了X射线结晶学的表征。这两种抑制物结合在IL-2上的同一位置，与IL-2Rα的结合界面重合，并涉及与IL-2上的一些氨基酸残基的相互作用，这些氨基酸残基构成了IL-2/IL-2Rα结合的能量热点。结果表明，小分子结合部位可分为两个亚基，第一个亚基是一个主要的极性和刚性口袋，第二个亚基是一个高度适应的疏水区。 已知的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还没有被系统地阐明。我们将使用定量生化和生物物理分析以及X射线结晶学来测量来自这些已知IL-2抑制剂的不同分子片段的实验结合能和结合取向，并将结果与使用相同片段作为探针的计算结果进行比较。研究结果将提供有关物理化学和结构特征的新信息，这些特征使困难的PPI部位变得可下药，我们将使用这些信息来进一步改进我们的计算方法。

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.