Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/101852
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Type: Journal article
Title: Dual mechanism of Interleukin-3 receptor blockade by an anti-cancer antibody
Author: Broughton, S.
Hercus, T.
Hardy, M.
McClure, B.
Nero, T.
Dottore, M.
Huynh, H.
Braley, H.
Barry, E.
Kan, W.
Dhagat, U.
Scotney, P.
Hartman, D.
Busfield, S.
Owczarek, C.
Nash, A.
Wilson, N.
Parker, M.
Lopez, A.
Citation: Cell Reports, 2014; 8(2):410-419
Publisher: Cell Press
Issue Date: 2014
ISSN: 2211-1247
2211-1247
Statement of
Responsibility: 
Sophie E. Broughton, Timothy R. Hercus, Matthew P. Hardy, Barbara J. McClure, Tracy L. Nero, Mara Dottore, Huy Huynh, Hal Braley, Emma F. Barry, Winnie L. Kan, Urmi Dhagat, Pierre Scotney, Dallas Hartman, Samantha J. Busfield, Catherine M. Owczarek, Andrew D. Nash, Nicholas J. Wilson, Michael W. Parker, Angel F. Lopez
Abstract: 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.
Keywords: COS Cells
Animals
Cercopithecus aethiops
Humans
Antineoplastic Agents
Binding Sites, Antibody
Amino Acid Sequence
Protein Binding
Molecular Sequence Data
Interleukin-3 Receptor alpha Subunit
HEK293 Cells
Antibodies, Monoclonal, Humanized
Rights: © 2014 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0/).
DOI: 10.1016/j.celrep.2014.06.038
Grant ID: NHMRC
Appears in Collections:Aurora harvest 7
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