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Blood, Vol. 95 No. 8 (April 15), 2000:
pp. 2491-2498
PLENARY PAPER
Structure of the activation domain of the GM-CSF/IL-3/IL-5
receptor common  -chain bound to an antagonist
Jamie Rossjohn,
William J. McKinstry,
Joanna M. Woodcock,
Barbara J. McClure,
Timothy R. Hercus,
Michael W. Parker,
Angel F. Lopez, and
Christopher J. Bagley
From the Ian Potter Foundation Protein Crystallography
Laboratory, St. Vincent's Institute of Medical Research, Fitzroy,
Victoria, Australia; the Cytokine Receptor Laboratory and the
Protein Laboratory, Hanson Centre for Cancer Research,
Institute of Medical and Veterinary Science, Adelaide, South Australia,
Australia; and the Royal Adelaide Hospital, Adelaide, South Australia,
Australia.
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  -chain
(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 c also suggests how different
cytokines recognize a single receptor subunit, which may have
implications for homologous receptor systems.
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