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| | <StructureSection load='3hmw' size='340' side='right'caption='[[3hmw]], [[Resolution|resolution]] 3.00Å' scene=''> | | <StructureSection load='3hmw' size='340' side='right'caption='[[3hmw]], [[Resolution|resolution]] 3.00Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3hmw]] 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=3HMW OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=3HMW FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3hmw]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3HMW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3HMW FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CD:CADMIUM+ION'>CD</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]] 3Å</td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=3hmw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3hmw OCA], [http://pdbe.org/3hmw PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3hmw RCSB], [http://www.ebi.ac.uk/pdbsum/3hmw PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3hmw ProSAT]</span></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CD:CADMIUM+ION'>CD</scene></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=3hmw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3hmw OCA], [https://pdbe.org/3hmw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3hmw RCSB], [https://www.ebi.ac.uk/pdbsum/3hmw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3hmw ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
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| | <jmolCheckbox> | | <jmolCheckbox> |
| | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/hm/3hmw_consurf.spt"</scriptWhenChecked> | | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/hm/3hmw_consurf.spt"</scriptWhenChecked> |
| - | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked> |
| | <text>to colour the structure by Evolutionary Conservation</text> | | <text>to colour the structure by Evolutionary Conservation</text> |
| | </jmolCheckbox> | | </jmolCheckbox> |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Luo, J]] | + | [[Category: Luo J]] |
| - | [[Category: Antibody]]
| + | |
| - | [[Category: Cnto1275]]
| + | |
| - | [[Category: Fab]]
| + | |
| - | [[Category: Il-12]]
| + | |
| - | [[Category: Il-23]]
| + | |
| - | [[Category: Immune system]]
| + | |
| - | [[Category: Monoclonal antibody]]
| + | |
| - | [[Category: Ustekinumab]]
| + | |
| Structural highlights
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
Interleukin (IL)-12 and IL-23 are heterodimeric proinflammatory cytokines that share a common p40 subunit, paired with p35 and p19 subunits, respectively. They represent an attractive class of therapeutic targets for the treatment of psoriasis and other immune-mediated diseases. Ustekinumab is a fully human monoclonal antibody (mAb) that binds specifically to IL-12/IL-23p40 and neutralizes human IL-12 and IL-23 bioactivity. The crystal structure of ustekinumab Fab (antigen binding fragment of mAb), in complex with human IL-12, has been determined by X-ray crystallography at 3.0 A resolution. Ustekinumab Fab binds the D1 domain of the p40 subunit in a 1:1 ratio in the crystal, consistent with a 2 cytokines:1 mAb stoichiometry, as measured by isothermal titration calorimetry. The structure indicates that ustekinumab binds to the same epitope on p40 in both IL-12 and IL-23 with identical interactions. Mutational analyses confirm that several residues identified in the IL-12/IL-23p40 epitope provide important molecular binding interactions with ustekinumab. The electrostatic complementarity between the mAb antigen binding site and the p40 D1 domain epitope appears to play a key role in antibody/antigen recognition specificity. Interestingly, this structure also reveals significant structural differences in the p35 subunit and p35/p40 interface, compared with the published crystal structure of human IL-12, suggesting unusual and potentially functionally relevant structural flexibility of p35, as well as p40/p35 recognition. Collectively, these data describe unique observations about IL-12p35 and ustekinumab interactions with p40 that account for its dual binding and neutralization of IL-12 and IL-23.
Structural basis for the dual recognition of IL-12 and IL-23 by ustekinumab.,Luo J, Wu SJ, Lacy ER, Orlovsky Y, Baker A, Teplyakov A, Obmolova G, Heavner GA, Richter HT, Benson J J Mol Biol. 2010 Oct 8;402(5):797-812. Epub 2010 Aug 4. PMID:20691190[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Luo J, Wu SJ, Lacy ER, Orlovsky Y, Baker A, Teplyakov A, Obmolova G, Heavner GA, Richter HT, Benson J. Structural basis for the dual recognition of IL-12 and IL-23 by ustekinumab. J Mol Biol. 2010 Oct 8;402(5):797-812. Epub 2010 Aug 4. PMID:20691190 doi:10.1016/j.jmb.2010.07.046
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