Kalai M, Montero-Julian F A, Grötzinger J, Fontaine V, Vandenbussche P, Deschuyteneer R, Wollmer A, Brailly H, Content J
Institut Pasteur de Bruxelles, Département de Virologie, Belgium.
Blood. 1997 Feb 15;89(4):1319-33.
The interaction between interleukin-6 (IL-6) and IL-6 receptor (IL-6R) is the initial and most specific step in the IL-6 signaling pathway. Understanding its mechanism at the amino acid level is the basis for developing small IL-6-inhibiting molecules. We studied the human IL-6 (hIL-6)/hIL-6R binding interface by a combination of molecular modelling and site-directed mutagenesis. Our model suggests that the center of the interface between the two molecules consists of hydrophobic contacts predicted to account for most of the binding-free energy. These contacts can be regarded as a hydrophobic core shielded by hydrophilic residues that are also needed for recognition. Following this hypothesis, we altered in hIL-6 and hIL-6R residues predicted to reside in the contact region and to interact with each other. We studied the capacity of these mutants to form an IL-6/IL-6R complex and their ability to transduce the signal. This combined approach has led to the identification of certain residue-clusters in the binding interface and to a rational explanation of their specific interactions, suggesting therein a likely mechanism of complex formation. The results confirm the predictive model and strongly support our hypothesis. Comparison with other cytokines and their alpha-subunit receptors suggests that the structural location of certain binding sites are conserved.
白细胞介素-6（IL-6）与白细胞介素-6受体（IL-6R）之间的相互作用是IL-6信号通路的起始且最具特异性的步骤。在氨基酸水平上理解其机制是开发小型IL-6抑制分子的基础。我们通过分子建模和定点诱变相结合的方法研究了人IL-6（hIL-6）/hIL-6R的结合界面。我们的模型表明，两个分子之间界面的中心由疏水接触组成，预计这些疏水接触占结合自由能的大部分。这些接触可被视为一个疏水核心，被识别所需的亲水性残基所屏蔽。根据这一假设，我们改变了hIL-6和hIL-6R中预计位于接触区域且相互作用的残基。我们研究了这些突变体形成IL-6/IL-6R复合物的能力及其转导信号的能力。这种综合方法已导致在结合界面中鉴定出某些残基簇，并对它们的特异性相互作用作出了合理的解释，由此暗示了复合物形成的可能机制。结果证实了预测模型，并有力地支持了我们的假设。与其他细胞因子及其α亚基受体的比较表明，某些结合位点的结构位置是保守的。
