title: Structural basis for the blockage of IL-2 signaling by therapeutic antibody basiliximab.
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.
authors.affiliation: State Key Laboratory of Molecular Biology, Research Center for Structural Biology, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Jiamu
authors.initials: J
authors.lastname: Du
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
authors.forename: Dapeng
authors.initials: D
authors.lastname: Zhang
authors.forename: Jianchuan
authors.initials: J
authors.lastname: Wang
authors.forename: Huaizu
authors.initials: H
authors.lastname: Guo
authors.forename: Baozhen
authors.initials: B
authors.lastname: Peng
authors.forename: Yajun
authors.initials: Y
authors.lastname: Guo
authors.forename: Jianping
authors.initials: J
authors.lastname: Ding
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D000915:Antibody Affinity; D000077552:Basiliximab; D001666:Binding Sites, Antibody; D003460:Crystallization; D018360:Crystallography, X-Ray; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D007376:Interleukin-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D018448:Models, Immunological; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D015398:Signal Transduction / Q000276:immunology*
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D007140:Immunoglobulin Fab Fragments; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D011993:Recombinant Fusion Proteins; D000077552:Basiliximab