3IU3

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

Summary for 3IU3

• Entry DOI: 10.2210/pdb3iu3/pdb
• Descriptor: Heavy chain of Fab fragment of Basiliximab, Light chain of Fab fragment of Basiliximab, Interleukin-2 receptor alpha chain, ... (4 entities in total)
• Functional Keywords: il-2ra, cd25, basiliximab, simulect, therapeutic antibody, disulfide bond, glycoprotein, membrane, receptor, sushi, transmembrane, immune system
• Biological source: Mus musculus, Homo sapiens (mouse, human); More
• Cellular location: Membrane; Single-pass type I membrane protein: P01589
• Total number of polymer chains: 9
• Total formula weight: 216006.16

Authors

Du, J.,Yang, H.,Wang, J.,Ding, J. (deposition date: 2009-08-29, release date: 2010-01-26, Last modification date: 2024-10-16)

Primary citation

Du, J.,Yang, H.,Zhang, D.,Wang, J.,Guo, H.,Peng, B.,Guo, Y.,Ding, J.
Structural basis for the blockage of IL-2 signaling by therapeutic antibody basiliximab
J.Immunol., 184:1361-1368, 2010

PubMed Abstract: IL-2 signaling plays a central role in the initiation and activation of immune responses. Correspondingly, blockage of this pathway leads to inhibition of the immune system and would provide some therapeutic benefits. Basiliximab (Simulect), a therapeutic mAb drug with specificity against IL-2R alpha of T cells, was approved by U.S. Food and Drug Administration in 1998. It has been proven to be effective in the suppression of the IL-2 pathway and hence has been widely used to prevent allograft rejection in organ transplantation, especially in kidney transplants. In this study, we report the crystal structure of the basiliximab Fab in complex with the ectodomain of IL-2R alpha at 2.9 A resolution. In the complex structure, the Fab interacts with IL-2R alpha with extensive hydrophobic and hydrophilic interactions, accounting for a high binding affinity of 0.14 nM. The Ag binding site of basiliximab consists of all six CDR loops that form a large binding interface with a central shallow hydrophobic groove surrounded by four hydrophilic patches. The discontinuous epitope is composed of several segments from the D1 domain and a minor segment from the D2 domain that overlap with most of the regions responsible for the interactions with IL-2. Thus, basiliximab binding can completely block the interactions of IL-2 with IL-2R alpha and hence inhibit the activation of the IL-2 signal pathway. The structural results also provide important implications for the development of improved and new IL-2R alpha-targeted mAb drugs.

PubMed: 20032294
DOI: 10.4049/jimmunol.0903178

Experimental method

X-RAY DIFFRACTION (2.9 Å)