4JZJ

Crystal Structure of Receptor-Fab Complex

Summary for 4JZJ

• Entry DOI: 10.2210/pdb4jzj/pdb
• Descriptor: Interleukin-3 receptor subunit alpha, Fab Heavy Chain, Fab Light Chain, ... (9 entities in total)
• Functional Keywords: receptor-fab complex, cytokine receptor-immune system complex, cytokine receptor/immune system
• Biological source: Homo sapiens (human); More
• Cellular location: Membrane; Single-pass type I membrane protein: P26951
• Total number of polymer chains: 6
• Total formula weight: 165530.21

Authors

Broughton, S.E.,Parker, M.W. (deposition date: 2013-04-03, release date: 2014-04-09, Last modification date: 2024-10-16)

Primary citation

Broughton, S.E.,Hercus, T.R.,Hardy, M.P.,McClure, B.J.,Nero, T.L.,Dottore, M.,Huynh, H.,Braley, H.,Barry, E.F.,Kan, W.L.,Dhagat, U.,Scotney, P.,Hartman, D.,Busfield, S.J.,Owczarek, C.M.,Nash, A.D.,Wilson, N.J.,Parker, M.W.,Lopez, A.F.
Dual mechanism of interleukin-3 receptor blockade by an anti-cancer antibody
Cell Rep, 8:410-419, 2014

PubMed 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.

PubMed: 25043189
DOI: 10.1016/j.celrep.2014.06.038

Experimental method

X-RAY DIFFRACTION (2.801 Å)