Dual Mechanism of Interleukin-3 Receptor Blockade by an Anti-Cancer Antibody
| Autor: | Matthew P. Hardy, Emma F Barry, Catherine M. Owczarek, Mara Dottore, Michael W. Parker, Urmi Dhagat, Dallas Hartman, Hal Braley, Winnie L. Kan, Tracy L. Nero, Angel F. Lopez, Samantha J. Busfield, Nicholas J. Wilson, Pierre Scotney, Barbara J. McClure, Sophie E. Broughton, Andrew D. Nash, Huy Huynh, Timothy R. Hercus |
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| Přispěvatelé: | Broughton, Sophie E, Hercus, Timothy R, Hardy, Matthew P, McClure, Barbara J, Nero, Tracy L, Dottore, Mara, Huyhn, Huy, Braley, Hal, Barry, Emma F, Kan, Winnie L, Dhagat, Urmi, Scotney, Pierre, Hartman, Dallas, Busfield, Samantha J, Owczarek, Catherine M, Nash, Andrew D, Wilson, Nicholas J, Parker, Michael W, Lopez, Angel F |
| Jazyk: | angličtina |
| Předmět: |
T cell
Molecular Sequence Data Interleukin-3 Receptor alpha Subunit Antineoplastic Agents Plasma protein binding Biology Antibodies Monoclonal Humanized General Biochemistry Genetics and Molecular Biology Epitope Chlorocebus aethiops medicine cancer Animals Humans Amino Acid Sequence Binding site Receptor lcsh:QH301-705.5 Molecular biology Cell biology HEK293 Cells medicine.anatomical_structure lcsh:Biology (General) Interleukin-21 receptor leukaemia COS Cells Binding Sites Antibody Interleukin-3 receptor Cytokine receptor human IL-3 receptor Protein Binding |
| Zdroj: | Cell Reports, Vol 8, Iss 2, Pp 410-419 (2014) |
| ISSN: | 2211-1247 |
| DOI: | 10.1016/j.celrep.2014.06.038 |
| Popis: | 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. Refereed/Peer-reviewed |
| Databáze: | OpenAIRE |
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