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| | ==Crystal structure of the therapeutic antibody binding fragment of gevokizumab in its unbound state== | | ==Crystal structure of the therapeutic antibody binding fragment of gevokizumab in its unbound state== |
| - | <StructureSection load='4g6k' size='340' side='right' caption='[[4g6k]], [[Resolution|resolution]] 1.90Å' scene=''> | + | <StructureSection load='4g6k' size='340' side='right'caption='[[4g6k]], [[Resolution|resolution]] 1.90Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4g6k]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4G6K OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4G6K FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4g6k]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4G6K OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4G6K FirstGlance]. <br> |
| - | </td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4g6j|4g6j]], [[4g6m|4g6m]], [[4g5z|4g5z]]</td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.9Å</td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4g6k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4g6k OCA], [http://pdbe.org/4g6k PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4g6k RCSB], [http://www.ebi.ac.uk/pdbsum/4g6k PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4g6k ProSAT]</span></td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4g6k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4g6k OCA], [https://pdbe.org/4g6k PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4g6k RCSB], [https://www.ebi.ac.uk/pdbsum/4g6k PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4g6k ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
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| | ==See Also== | | ==See Also== |
| - | *[[3D structures of monoclonal antibody|3D structures of monoclonal antibody]] | + | *[[Monoclonal Antibodies 3D structures|Monoclonal Antibodies 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Blech, M]] | + | [[Category: Large Structures]] |
| - | [[Category: Hoerer, S]] | + | [[Category: Mus musculus]] |
| - | [[Category: Cytokine]] | + | [[Category: Blech M]] |
| - | [[Category: Immune system]] | + | [[Category: Hoerer S]] |
| - | [[Category: Immunoglobulin fold]]
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| - | [[Category: Interleukine-1beta]]
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| Structural highlights
Publication Abstract from PubMed
Interleukin-1beta (IL-1beta) is a key orchestrator in inflammatory and several immune responses. IL-1beta exerts its effects through interleukin-1 receptor type I (IL-1RI) and interleukin-1 receptor accessory protein (IL-1RAcP), which together form a heterotrimeric signaling-competent complex. Canakinumab and gevokizumab are highly specific IL-1beta monoclonal antibodies. Canakinumab is known to neutralize IL-1beta by competing for binding to IL-1R and therefore blocking signaling by the antigen:antibody complex. Gevokizumab is claimed to be a regulatory therapeutic antibody that modulates IL-1beta bioactivity by reducing the affinity for its IL-1RI:IL-1RAcP signaling complex. How IL-1beta signaling is affected by both canakinumab and gevokizumab was not yet experimentally determined. We have analyzed the crystal structures of canakinumab and gevokizumab antibody binding fragment (Fab) as well as of their binary complexes with IL-1beta. Furthermore, we characterized the epitopes on IL-1beta employed by the antibodies by NMR epitope mapping studies. The direct comparison of NMR and X-ray data shows that the epitope defined by the crystal structure encompasses predominantly those residues whose NMR resonances are severely perturbed upon complex formation. The antigen:Fab co-structures confirm the previously identified key contact residues on IL-1beta and provide insight into the mechanisms leading to their distinct modulation of IL-1beta signaling. A significant steric overlap of the binding interfaces of IL-1R and canakinumab on IL-1beta causes competitive inhibition of the association of IL-1beta and its receptor. In contrast, gevokizumab occupies an allosteric site on IL-1beta and complex formation results in a minor reduction of binding affinity to IL-1RI. This suggests two different mechanisms of IL-1beta pathway attenuation.
One Target-Two Different Binding Modes: Structural Insights into Gevokizumab and Canakinumab Interactions to Interleukin-1beta,Blech M, Peter D, Fischer P, Bauer MM, Hafner M, Zeeb M, Nar H J Mol Biol. 2012 Oct 3. pii: S0022-2836(12)00786-3. doi:, 10.1016/j.jmb.2012.09.021. PMID:23041424[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Blech M, Peter D, Fischer P, Bauer MM, Hafner M, Zeeb M, Nar H. One Target-Two Different Binding Modes: Structural Insights into Gevokizumab and Canakinumab Interactions to Interleukin-1beta J Mol Biol. 2012 Oct 3. pii: S0022-2836(12)00786-3. doi:, 10.1016/j.jmb.2012.09.021. PMID:23041424 doi:10.1016/j.jmb.2012.09.021
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