3NFP

Crystal structure of the Fab fragment of therapeutic antibody daclizumab in complex with IL-2Ra (CD25) ectodomain

Summary for 3NFP

• Entry DOI: 10.2210/pdb3nfp/pdb
• Related: 3IU3 3NFS
• Descriptor: Heavy chain of Fab fragment of daclizumab, Light chain of Fab fragment of daclizumab, Interleukin-2 receptor subunit alpha, ... (4 entities in total)
• Functional Keywords: il-2ra, cd25, daclizumab, zenapax, therapeutic antibody, immune system, immune system-cytokine complex, immune system/cytokine
• Biological source: Homo sapiens (human); More
• Cellular location: Membrane; Single-pass type I membrane protein: P01589
• Total number of polymer chains: 6
• Total formula weight: 143115.39

Authors

Yang, H.,Wang, J.,Du, J.,Zhong, C.,Guo, Y.,Ding, J. (deposition date: 2010-06-10, release date: 2010-09-15, Last modification date: 2024-10-30)

Primary citation

Yang, H.,Wang, J.,Du, J.,Zhong, C.,Zhang, D.,Guo, H.,Guo, Y.,Ding, J.
Structural basis of immunosuppression by the therapeutic antibody daclizumab
Cell Res., 20:1361-1371, 2010

PubMed Abstract: 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-2Rα. 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-2Rα ectodomain at 2.6 and 2.8 Å resolution, respectively. The daclizumab Fab adopts a similar conformation in the presence or absence of the IL-2Rα 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-2Rα ectodomain, a large portion of which overlaps with the regions that interact with IL-2, suggesting that the binding of daclizumab to IL-2Rα would prevent the IL-2 binding to IL-2Rα and the subsequent formation of the IL-2/IL-2Rαβγ(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-2Rα.

PubMed: 20820193
DOI: 10.1038/cr.2010.130

Experimental method

X-RAY DIFFRACTION (2.86 Å)