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| - | ==CRYSTAL STRUCTURE OF HUMAN IL-18 COMPLEXED TO MURINE REFERENCE ANTIBODY 125-2H FAB== | + | |
| - | <StructureSection load='2vxt' size='340' side='right' caption='[[2vxt]], [[Resolution|resolution]] 1.49Å' scene=''> | + | ==Crystal structure of human IL-18 complexed to murine reference antibody 125-2H Fab== |
| | + | <StructureSection load='2vxt' size='340' side='right'caption='[[2vxt]], [[Resolution|resolution]] 1.49Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2vxt]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human] and [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2VXT OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2VXT FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2vxt]] is a 3 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=2VXT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2VXT FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></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]] 1.49Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1j0s|1j0s]], [[2vxu|2vxu]], [[2vxv|2vxv]]</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></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=2vxt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2vxt OCA], [http://pdbe.org/2vxt PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2vxt RCSB], [http://www.ebi.ac.uk/pdbsum/2vxt PDBsum]</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=2vxt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2vxt OCA], [https://pdbe.org/2vxt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2vxt RCSB], [https://www.ebi.ac.uk/pdbsum/2vxt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2vxt ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/IL18_HUMAN IL18_HUMAN]] Augments natural killer cell activity in spleen cells and stimulates interferon gamma production in T-helper type I cells. | + | [https://www.uniprot.org/uniprot/IL18_HUMAN IL18_HUMAN] Augments natural killer cell activity in spleen cells and stimulates interferon gamma production in T-helper type I cells. |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
| | Check<jmol> | | Check<jmol> |
| | <jmolCheckbox> | | <jmolCheckbox> |
| - | <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/vx/2vxt_consurf.spt"</scriptWhenChecked> | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/vx/2vxt_consurf.spt"</scriptWhenChecked> |
| | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> |
| | <text>to colour the structure by Evolutionary Conservation</text> | | <text>to colour the structure by Evolutionary Conservation</text> |
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| | ==See Also== | | ==See Also== |
| - | *[[Interleukin|Interleukin]] | + | *[[Interleukin 3D structures|Interleukin 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Lk3 transgenic mice]] | + | [[Category: Large Structures]] |
| - | [[Category: Argiriadi, M A]] | + | [[Category: Mus musculus]] |
| - | [[Category: Borhani, D W]] | + | [[Category: Argiriadi MA]] |
| - | [[Category: Ghayur, T]] | + | [[Category: Borhani DW]] |
| - | [[Category: Wu, C]] | + | [[Category: Ghayur T]] |
| - | [[Category: Xiang, T]] | + | [[Category: Wu C]] |
| - | [[Category: Autoimmunity]]
| + | [[Category: Xiang T]] |
| - | [[Category: Cytokine]]
| + | |
| - | [[Category: Fab]]
| + | |
| - | [[Category: Glycoprotein]]
| + | |
| - | [[Category: Il-18]]
| + | |
| - | [[Category: Immunoglobulin domain]]
| + | |
| - | [[Category: Immunoglobulin v region]]
| + | |
| - | [[Category: Secreted]]
| + | |
| - | [[Category: Th1/th2 cell]]
| + | |
| Structural highlights
Function
IL18_HUMAN Augments natural killer cell activity in spleen cells and stimulates interferon gamma production in T-helper type I cells.
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
The unique cytokine interleukin-18 (IL-18) acts synergistically with IL-12 to regulate T-helper 1 and 2 lymphocytes and, as such, seems to underlie the pathogenesis of various autoimmune and allergic diseases. Several anti-IL-18 agents are in clinical development, including the recombinant human antibody ABT-325, which is entering trials for autoimmune diseases. Given competing cytokine/receptor and cytokine/receptor decoy interactions, understanding the structural basis for recognition is critical for effective development of anti-cytokine therapies. Here we report three crystal structures: the murine antibody 125-2H Fab fragment bound to human IL-18, at 1.5 A resolution; the 125-2H Fab (2.3 A); and the ABT-325 Fab (1.5 A). These structures, along with human/mouse IL-18 chimera binding data, allow us to make three key observations relevant to the biology and antigenic recognition of IL-18 and related cytokines. First, several IL-18 residues shift dramatically (> 10 A) upon binding 125-2H, compared with unbound IL-18 (Kato, Z., Jee, J., Shikano, H., Mishima, M., Ohki, I., Ohnishi, H., Li, A., Hashimoto, K., Matsukuma, E., Omoya, K., Yamamoto, Y., Yoneda, T., Hara, T., Kondo, N., and Shirakawa, M. (2003) Nat. Struct. Biol. 10, 966-971). IL-18 thus exhibits plasticity that may be common to its interactions with other receptors. Related cytokines may exhibit similar plasticity. Second, ABT-325 and 125-2H differ significantly in combining site character and architecture, thus explaining their ability to bind IL-18 simultaneously at distinct epitopes. These data allow us to define the likely ABT-325 epitope and thereby explain the distinct neutralizing mechanisms of both antibodies. Third, given the high 125-2H potency, 10 well ordered water molecules are trapped upon complex formation in a cavity between two IL-18 loops and all six 125-2H complementarity-determining regions. Thus, counterintuitively, tight and specific antibody binding may in some cases be water-mediated.
Unusual water-mediated antigenic recognition of the proinflammatory cytokine interleukin-18.,Argiriadi MA, Xiang T, Wu C, Ghayur T, Borhani DW J Biol Chem. 2009 Sep 4;284(36):24478-89. Epub 2009 Jun 24. PMID:19553661[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Argiriadi MA, Xiang T, Wu C, Ghayur T, Borhani DW. Unusual water-mediated antigenic recognition of the proinflammatory cytokine interleukin-18. J Biol Chem. 2009 Sep 4;284(36):24478-89. Epub 2009 Jun 24. PMID:19553661 doi:10.1074/jbc.M109.023887
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