hIL-6与其受体作用的结构基础及拮抗剂的研究进展

通过对大量的分子生物学实验及晶体衍射结果的分析 ,从分子水平揭示人白细胞介素 6(hIL 6 )与其受体相互作用的结构模式及结合表位 .hIL 6属于促红细胞生成素受体超家族 ,首先和hIL 6受体α低亲和力结合 ,两者形成的复合物再与hIL 6受体 β(gp130 )的胞外区相互作用形成高亲和力三聚体 ,但是hIL 6不能单独和gp130结合 ,需要借助于hIL 6受体α的桥梁作用才能将二者联系起来进而促进六聚体的形成 .hIL 6是一种能够介导细胞表面信号转导 ,调节机体免疫及造血干细胞增殖和分化的细胞因子 ,许多疾病的发病机理及发展进程都和hIL 6过表达有关 .基于对hIL 6与其受体相互作用方式的探究 ,为hIL 6小分子拮抗剂的药物设计提供了理论模型 ,在此基础上已研究开发了许多不同种类的hIL 6新型分子拮抗剂 ,其中部分拮抗剂已应用于临床指导 .

Advances in Structural Base of Interaction Between hIL-6 and Its Receptor and Antagonist of hIL-6

By the molecular biological mutant experiments and crystal diffraction analysis,an interaction mode and binding epitopes between the human interleukin-6(hIL-6) and its receptor were determined. The results showed that the hIL-6 recognized hIL-6 receptor(hIL-6R) at a low affinity,and then the complex formed by the hIL-6 and the hIL-6R could bind to the extracellular region of gp130 at a high affinity.The hIL-6 could not bind with gp130 solely. However, the hIL-6R looks like a bridge of hIL-6 and gp130 to form a hexameric complex.The hIL-6 was an immunoregulatory cytokine that could activate cell surface signaling and involved in the regulation of proliferation and differentiation in hematopoietic cells.The hIL-6 was involved in the pathogenesis and maintenance of several diseases. The interaction between hIL-6 and hIL-6R offeres a theoretical model for designing molecular antagonists,and a series of novel molecular antagonists of the hIL-6 have been used in clinic.