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| | ==Crystal structure of the Fab fragment of therapeutic antibody daclizumab in complex with IL-2Ra (CD25) ectodomain== | | ==Crystal structure of the Fab fragment of therapeutic antibody daclizumab in complex with IL-2Ra (CD25) ectodomain== |
| - | <StructureSection load='3nfp' size='340' side='right' caption='[[3nfp]], [[Resolution|resolution]] 2.86Å' scene=''> | + | <StructureSection load='3nfp' size='340' side='right'caption='[[3nfp]], [[Resolution|resolution]] 2.86Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3nfp]] is a 6 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=3NFP OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3NFP FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3nfp]] is a 6 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=3NFP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3NFP FirstGlance]. <br> |
| - | </td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3iu3|3iu3]], [[3nfs|3nfs]]</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]] 2.86Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">IL2RA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=3nfp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3nfp OCA], [https://pdbe.org/3nfp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3nfp RCSB], [https://www.ebi.ac.uk/pdbsum/3nfp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3nfp ProSAT]</span></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=3nfp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3nfp OCA], [http://pdbe.org/3nfp PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3nfp RCSB], [http://www.ebi.ac.uk/pdbsum/3nfp PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3nfp ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/IL2RA_HUMAN IL2RA_HUMAN]] Genetic variations in IL2RA are associated with susceptibility to diabetes mellitus insulin-dependent type 10 (IDDM10) [MIM:[http://omim.org/entry/601942 601942]]. A multifactorial disorder of glucose homeostasis that is characterized by susceptibility to ketoacidosis in the absence of insulin therapy. Clinical fetaures are polydipsia, polyphagia and polyuria which result from hyperglycemia-induced osmotic diuresis and secondary thirst. These derangements result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels.<ref>PMID:17676041</ref> | + | [https://www.uniprot.org/uniprot/IL2RA_HUMAN IL2RA_HUMAN] Genetic variations in IL2RA are associated with susceptibility to diabetes mellitus insulin-dependent type 10 (IDDM10) [MIM:[https://omim.org/entry/601942 601942]. A multifactorial disorder of glucose homeostasis that is characterized by susceptibility to ketoacidosis in the absence of insulin therapy. Clinical fetaures are polydipsia, polyphagia and polyuria which result from hyperglycemia-induced osmotic diuresis and secondary thirst. These derangements result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels.<ref>PMID:17676041</ref> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/IL2RA_HUMAN IL2RA_HUMAN]] Receptor for interleukin-2. | + | [https://www.uniprot.org/uniprot/IL2RA_HUMAN IL2RA_HUMAN] Receptor for interleukin-2. |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | ==See Also== | | ==See Also== |
| - | *[[Interleukin receptor|Interleukin receptor]] | + | *[[Interleukin receptor 3D structures|Interleukin receptor 3D structures]] |
| | *[[Monoclonal Antibodies 3D structures|Monoclonal Antibodies 3D structures]] | | *[[Monoclonal Antibodies 3D structures|Monoclonal Antibodies 3D structures]] |
| | == References == | | == References == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Ding, J]] | + | [[Category: Large Structures]] |
| - | [[Category: Du, J]] | + | [[Category: Ding J]] |
| - | [[Category: Guo, Y]] | + | [[Category: Du J]] |
| - | [[Category: Wang, J]] | + | [[Category: Guo Y]] |
| - | [[Category: Yang, H]] | + | [[Category: Wang J]] |
| - | [[Category: Zhong, C]] | + | [[Category: Yang H]] |
| - | [[Category: Cd25]]
| + | [[Category: Zhong C]] |
| - | [[Category: Daclizumab]]
| + | |
| - | [[Category: Il-2ra]]
| + | |
| - | [[Category: Immune system]]
| + | |
| - | [[Category: Immune system-cytokine complex]]
| + | |
| - | [[Category: Therapeutic antibody]]
| + | |
| - | [[Category: Zenapax]]
| + | |
| Structural highlights
Disease
IL2RA_HUMAN Genetic variations in IL2RA are associated with susceptibility to diabetes mellitus insulin-dependent type 10 (IDDM10) [MIM:601942. A multifactorial disorder of glucose homeostasis that is characterized by susceptibility to ketoacidosis in the absence of insulin therapy. Clinical fetaures are polydipsia, polyphagia and polyuria which result from hyperglycemia-induced osmotic diuresis and secondary thirst. These derangements result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels.[1]
Function
IL2RA_HUMAN Receptor for interleukin-2.
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-2 (IL)-2 signaling plays a pivotal role in the activation of immune responses, and drugs that block this pathway have been shown to be effective for the immunosuppression in patients with organ transplantation to alleviate/eliminate allograft rejection. The first humanized monoclonal antibody (mAb) daclizumab falls into this category and shows high specificity and affinity against a key component of the IL-2 receptor complex, namely IL-2Ralpha. To reveal the molecular mechanism of the inhibition of the IL-2 signaling pathway by daclizumab, we determined the crystal structures of the daclizumab Fab in free form and in complex with the IL-2Ralpha ectodomain at 2.6 and 2.8 A resolution, respectively. The daclizumab Fab adopts a similar conformation in the presence or absence of the IL-2Ralpha ectodomain. The antigen-binding site of daclizumab is mainly composed of five complementarity determining regions (CDRs) that form a large positively charged surface depression and two flanking patches that are generally hydrophobic. The conformational epitope consists of several discontinuous segments of the IL-2Ralpha ectodomain, a large portion of which overlaps with the regions that interact with IL-2, suggesting that the binding of daclizumab to IL-2Ralpha would prevent the IL-2 binding to IL-2Ralpha and the subsequent formation of the IL-2/IL-2Ralphabetagamma(c) complex, and therefore block the IL-2 signaling pathway. These results also have implications for the design and development of improved mAb drugs targeting IL-2Ralpha.Cell Research advance online publication 7 September 2010; doi:10.1038/cr.2010.130.
Structural basis of immunosuppression by the therapeutic antibody daclizumab.,Yang H, Wang J, Du J, Zhong C, Zhang D, Guo H, Guo Y, Ding J Cell Res. 2010 Sep 7. PMID:20820193[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Lowe CE, Cooper JD, Brusko T, Walker NM, Smyth DJ, Bailey R, Bourget K, Plagnol V, Field S, Atkinson M, Clayton DG, Wicker LS, Todd JA. Large-scale genetic fine mapping and genotype-phenotype associations implicate polymorphism in the IL2RA region in type 1 diabetes. Nat Genet. 2007 Sep;39(9):1074-82. Epub 2007 Aug 5. PMID:17676041 doi:10.1038/ng2102
- ↑ Yang H, Wang J, Du J, Zhong C, Zhang D, Guo H, Guo Y, Ding J. Structural basis of immunosuppression by the therapeutic antibody daclizumab. Cell Res. 2010 Sep 7. PMID:20820193 doi:10.1038/cr.2010.130
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