1egj
From Proteopedia
(New page: 200px<br /> <applet load="1egj" size="450" color="white" frame="true" align="right" spinBox="true" caption="1egj, resolution 2.8Å" /> '''DOMAIN 4 OF THE BETA...) |
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| - | [[Image:1egj.gif|left|200px]]<br /> | + | [[Image:1egj.gif|left|200px]]<br /><applet load="1egj" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="1egj" size=" | + | |
caption="1egj, resolution 2.8Å" /> | caption="1egj, resolution 2.8Å" /> | ||
'''DOMAIN 4 OF THE BETA COMMON CHAIN IN COMPLEX WITH AN ANTIBODY'''<br /> | '''DOMAIN 4 OF THE BETA COMMON CHAIN IN COMPLEX WITH AN ANTIBODY'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Heterodimeric cytokine receptors generally consist of a major | + | 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) |
==About this Structure== | ==About this Structure== | ||
| - | 1EGJ is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus] with NAG as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http:// | + | 1EGJ is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus] with <scene name='pdbligand=NAG:'>NAG</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1EGJ OCA]. |
==Reference== | ==Reference== | ||
| Line 15: | Line 14: | ||
[[Category: Mus musculus]] | [[Category: Mus musculus]] | ||
[[Category: Protein complex]] | [[Category: Protein complex]] | ||
| - | [[Category: Bagley, C | + | [[Category: Bagley, C J.]] |
| - | [[Category: Hercus, T | + | [[Category: Hercus, T R.]] |
| - | [[Category: Lopez, A | + | [[Category: Lopez, A F.]] |
| - | [[Category: McClure, B | + | [[Category: McClure, B J.]] |
| - | [[Category: McKinstry, W | + | [[Category: McKinstry, W J.]] |
| - | [[Category: Parker, M | + | [[Category: Parker, M W.]] |
[[Category: Rossjohn, J.]] | [[Category: Rossjohn, J.]] | ||
| - | [[Category: Woodcock, J | + | [[Category: Woodcock, J M.]] |
[[Category: NAG]] | [[Category: NAG]] | ||
[[Category: cytokine receptor complexed to an antibody]] | [[Category: cytokine receptor complexed to an antibody]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:27:30 2008'' |
Revision as of 10:27, 21 February 2008
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DOMAIN 4 OF THE BETA COMMON CHAIN IN COMPLEX WITH AN ANTIBODY
Overview
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)
About this Structure
1EGJ is a Protein complex structure of sequences from Homo sapiens and Mus musculus with as ligand. Full crystallographic information is available from OCA.
Reference
Structure of the activation domain of the GM-CSF/IL-3/IL-5 receptor common beta-chain bound to an antagonist., Rossjohn J, McKinstry WJ, Woodcock JM, McClure BJ, Hercus TR, Parker MW, Lopez AF, Bagley CJ, Blood. 2000 Apr 15;95(8):2491-8. PMID:10753826
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