Structural basis of immunosuppression by the therapeutic antibody daclizumab
文献类型：期刊论文
| 作者 | Yang, H; Wang, JC; Du, JM; Zhong, C; Zhang, DP; Guo, HZ; Guo, YJ; Ding, JP |
| 刊名 | CELL RESEARCH
 |
| 出版日期 | 2010 |
| 卷号 | 20期号:12页码:1361-1371 |
| 关键词 | IL-2R alpha IL-2 signaling daclizumab therapeutic antibody crystal structure |
| 通讯作者 | Ding, JP (reprint author), Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, State Key Lab Mol Biol, Shanghai 200031, Peoples R China.,jpding@sibs.ac.cn |
| 英文摘要 | Interleukin-2 (IL)-2 signaling plays a pivotal role in the activation of immune responses, and drugs that block this pathway have been shown to be effective for the immunosuppression in patients with organ transplantation to alleviate/eliminate allograft rejection. The first humanized monoclonal antibody (mAb) daclizumab falls into this category and shows high specificity and affinity against a key component of the IL-2 receptor complex, namely IL-2R alpha. To reveal the molecular mechanism of the inhibition of the IL-2 signaling pathway by daclizumab, we determined the crystal structures of the daclizumab Fab in free form and in complex with the IL-2R alpha ectodomain at 2.6 and 2.8 angstrom resolution, respectively. The daclizumab Fab adopts a similar conformation in the presence or absence of the IL-2R alpha ectodomain. The antigen-binding site of daclizumab is mainly composed of five complementarity determining regions (CDRs) that form a large positively charged surface depression and two flanking patches that are generally hydrophobic. The conformational epitope consists of several discontinuous segments of the IL-2R alpha ectodomain, a large portion of which overlaps with the regions that interact with IL-2, suggesting that the binding of daclizumab to IL-2Ra would prevent the IL-2 binding to IL-2R alpha and the subsequent formation of the IL-2/IL-2R alpha beta gamma(c) complex, and therefore block the IL-2 signaling pathway. These results also have implications for the design and development of improved mAb drugs targeting IL-2R alpha. |
| 学科主题 | Cell Biology |
| 类目[WOS] | Cell Biology |
| 关键词[WOS] | LIVER-TRANSPLANT RECIPIENTS ; VERSUS-HOST-DISEASE ; INTERLEUKIN-2 RECEPTOR ; CYTOKINE RECEPTOR ; ALPHA-RECEPTOR ; MYCOPHENOLATE-MOFETIL ; RENAL-TRANSPLANTATION ; INDUCTION THERAPY ; CRYSTAL-STRUCTURE ; IL-2 RECEPTOR |
| 收录类别 | SCI |
| 语种 | 英语 |
| WOS记录号 | WOS:000284867900009 |
| 版本 | 出版稿 |
| 源URL | [http://202.127.25.143/handle/331003/1078]  |
| 专题 | 上海生化细胞研究所_上海生科院生化细胞研究所 |
| 推荐引用方式 GB/T 7714 | Yang, H,Wang, JC,Du, JM,et al. Structural basis of immunosuppression by the therapeutic antibody daclizumab[J]. CELL RESEARCH,2010,20(12):1361-1371. |
| APA | Yang, H.,Wang, JC.,Du, JM.,Zhong, C.,Zhang, DP.,...&Ding, JP.(2010).Structural basis of immunosuppression by the therapeutic antibody daclizumab.CELL RESEARCH,20(12),1361-1371. |
| MLA | Yang, H,et al."Structural basis of immunosuppression by the therapeutic antibody daclizumab".CELL RESEARCH 20.12(2010):1361-1371. |
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