In:
Blood, American Society of Hematology, Vol. 95, No. 8 ( 2000-04-15), p. 2491-2498
Kurzfassung:
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 (βc) 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 βc also suggests how different cytokines recognize a single receptor subunit, which may have implications for homologous receptor systems.
Materialart:
Online-Ressource
ISSN:
1528-0020
,
0006-4971
DOI:
10.1182/blood.V95.8.2491.008k06_2491_2498
Sprache:
Englisch
Verlag:
American Society of Hematology
Publikationsdatum:
2000
ZDB Id:
1468538-3
ZDB Id:
80069-7
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