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PDBsum entry 4jzj
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Cytokine receptor/immune system
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PDB id
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4jzj
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Contents |
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250 a.a.
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214 a.a.
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219 a.a.
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References listed in PDB file
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Key reference
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Title
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Dual mechanism of interleukin-3 receptor blockade by an anti-Cancer antibody.
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Authors
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S.E.Broughton,
T.R.Hercus,
M.P.Hardy,
B.J.Mcclure,
T.L.Nero,
M.Dottore,
H.Huynh,
H.Braley,
E.F.Barry,
W.L.Kan,
U.Dhagat,
P.Scotney,
D.Hartman,
S.J.Busfield,
C.M.Owczarek,
A.D.Nash,
N.J.Wilson,
M.W.Parker,
A.F.Lopez.
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Ref.
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Cell Rep, 2014,
8,
410-419.
[DOI no: ]
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PubMed id
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Abstract
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Interleukin-3 (IL-3) is an activated T cell product that bridges innate and
adaptive immunity and contributes to several immunopathologies. Here, we report
the crystal structure of the IL-3 receptor α chain (IL3Rα) in complex with the
anti-leukemia antibody CSL362 that reveals the N-terminal domain (NTD), a domain
also present in the granulocyte-macrophage colony-stimulating factor (GM-CSF),
IL-5, and IL-13 receptors, adopting unique "open" and classical
"closed" conformations. Although extensive mutational analyses of the
NTD epitope of CSL362 show minor overlap with the IL-3 binding site, CSL362 only
inhibits IL-3 binding to the closed conformation, indicating alternative
mechanisms for blocking IL-3 signaling. Significantly, whereas
"open-like" IL3Rα mutants can simultaneously bind IL-3 and CSL362,
CSL362 still prevents the assembly of a higher-order IL-3 receptor-signaling
complex. The discovery of open forms of cytokine receptors provides the
framework for development of potent antibodies that can achieve a "double
hit" cytokine receptor blockade.
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