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https://hdl.handle.net/2440/9313
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Type: | Journal article |
Title: | Structure of the activation domain of the GM-CSF/IL-3/IL-5 receptor common b-chain bound to an antagonist |
Author: | Rossjohn, J. McKinstry, W. Woodcock, J. Mc Clure, B. Hercus, T. Parker, M. Lopez, A. Bagley, C. |
Citation: | Blood, 2000; 95(8):2491-2498 |
Publisher: | Amer Soc Hematology |
Issue Date: | 2000 |
ISSN: | 0006-4971 1528-0020 |
Statement of Responsibility: | Jamie Rossjohn, William J. McKinstry, Joanna M. Woodcock, Barbara J. McClure, Timothy R. Hercus, Michael W. Parker, Angel F. Lopez, and Christopher J. Bagley |
Abstract: | Heterodimeric cytokine receptors generally consist of a major cytokine-binding subunit and a signaling subunit. The latter can transduce signals by more than 1 cytokine, as exemplified by the granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2), and IL-6 receptor systems. However, often the signaling subunits in isolation are unable to bind cytokines, a fact that has made it more difficult to obtain structural definition of their ligand-binding sites. This report details the crystal structure of the ligand-binding domain of the GM-CSF/IL-3/IL-5 receptor beta-chain (beta(c)) signaling subunit in complex with the Fab fragment of the antagonistic monoclonal antibody, BION-1. This is the first single antagonist of all 3 known eosinophil-producing cytokines, and it is therefore capable of regulating eosinophil-related diseases such as asthma. The structure reveals a fibronectin type III domain, and the antagonist-binding site involves major contributions from the loop between the B and C strands and overlaps the cytokine-binding site. Furthermore, tyrosine(421) (Tyr(421)), a key residue involved in receptor activation, lies in the neighboring loop between the F and G strands, although it is not immediately adjacent to the cytokine-binding residues in the B-C loop. Interestingly, functional experiments using receptors mutated across these loops demonstrate that they are cooperatively involved in full receptor activation. The experiments, however, reveal subtle differences between the B-C loop and Tyr(421), which is suggestive of distinct functional roles. The elucidation of the structure of the ligand-binding domain of beta(c) also suggests how different cytokines recognize a single receptor subunit, which may have implications for homologous receptor systems. (Blood. 2000;95:2491-2498) |
Keywords: | Cell Line Humans Receptors, Granulocyte-Macrophage Colony-Stimulating Factor Receptors, Interleukin-3 Receptors, Interleukin Antibodies, Monoclonal Ligands Epitope Mapping Binding Sites Protein Conformation Protein Binding Molecular Sequence Data Receptors, Interleukin-5 |
DOI: | 10.1182/blood.v95.8.2491 |
Published version: | http://dx.doi.org/10.1182/blood.v95.8.2491 |
Appears in Collections: | Aurora harvest 4 Medicine publications |
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