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PDBsum entry 1egj
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Immune system
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PDB id
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1egj
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Contents |
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101 a.a.
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215 a.a.
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220 a.a.
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Structure of the activation domain of the gm-Csf/il-3/il-5 receptor common beta-Chain bound to an antagonist.
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Authors
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J.Rossjohn,
W.J.Mckinstry,
J.M.Woodcock,
B.J.Mcclure,
T.R.Hercus,
M.W.Parker,
A.F.Lopez,
C.J.Bagley.
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Ref.
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Blood, 2000,
95,
2491-2498.
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PubMed id
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Abstract
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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)
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