1EGJ

DOMAIN 4 OF THE BETA COMMON CHAIN IN COMPLEX WITH AN ANTIBODY

Summary for 1EGJ

• Entry DOI: 10.2210/pdb1egj/pdb
• Descriptor: CYTOKINE RECEPTOR COMMON BETA CHAIN PRECURSOR, ANTIBODY (LIGHT CHAIN), ANTIBODY (HEAVY CHAIN), ... (5 entities in total)
• Functional Keywords: cytokine receptor complexed to an antibody, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 59182.55

Authors

Rossjohn, J.,McKinstry, W.J.,Woodcock, J.M.,McClure, B.J.,Hercus, T.R.,Parker, M.W.,Lopez, A.F.,Bagley, C.J. (deposition date: 2000-02-15, release date: 2001-02-15, Last modification date: 2024-10-09)

Primary citation

Rossjohn, J.,McKinstry, W.J.,Woodcock, J.M.,McClure, B.J.,Hercus, T.R.,Parker, M.W.,Lopez, A.F.,Bagley, C.J.
Structure of the activation domain of the GM-CSF/IL-3/IL-5 receptor common beta-chain bound to an antagonist.
Blood, 95:2491-2498, 2000

PubMed Abstract: 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 beta-chain (beta(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, tyrosine(421) (Tyr(421)), 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 Tyr(421), which is suggestive of distinct functional roles. The elucidation of the structure of the ligand-binding domain of beta(c) also suggests how different cytokines recognize a single receptor subunit, which may have implications for homologous receptor systems. (Blood. 2000;95:2491-2498)

PubMed: 10753826

Experimental method

X-RAY DIFFRACTION (2.8 Å)