TY - JOUR
T1 - Structure of the activation domain of the GM-CSF/IL-3/IL-5 receptor common β-chain bound to an antagonist
AU - Rossjohn, Jamie
AU - McKinstry, William J.
AU - Woodcock, Joanna M.
AU - McClure, Barbara J.
AU - Hercus, Timothy R.
AU - Parker, Michael W.
AU - Lopez, Angel F.
AU - Bagley, Christopher J.
PY - 2000/4/15
Y1 - 2000/4/15
N2 - 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 β- chain (β(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, tyrosine421 (Tyr421), 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 Tyr421, which is suggestive of distinct functional roles. The elucidation of the structure of the ligand- binding domain of β(c) also suggests how different cytokines recognize a single receptor subunit, which may have implications for homologous receptor systems. (C) 2000 by The American Society of Hematology.
AB - 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 β- chain (β(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, tyrosine421 (Tyr421), 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 Tyr421, which is suggestive of distinct functional roles. The elucidation of the structure of the ligand- binding domain of β(c) also suggests how different cytokines recognize a single receptor subunit, which may have implications for homologous receptor systems. (C) 2000 by The American Society of Hematology.
UR - http://www.scopus.com/inward/record.url?scp=0034655647&partnerID=8YFLogxK
M3 - Article
C2 - 10753826
AN - SCOPUS:0034655647
VL - 95
SP - 2491
EP - 2498
JO - Blood
JF - Blood
SN - 0006-4971
IS - 8
ER -