View source for 3qaz


==IL-2 mutant D10 ternary complex==
<StructureSection load='3qaz' size='340' side='right'caption='[[3qaz]], [[Resolution|resolution]] 3.80&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[3qaz]] is a 36 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=3QAZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3QAZ FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.802&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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=3qaz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qaz OCA], [https://pdbe.org/3qaz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3qaz RCSB], [https://www.ebi.ac.uk/pdbsum/3qaz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3qaz ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/IL2_HUMAN IL2_HUMAN] Note=A chromosomal aberration involving IL2 is found in a form of T-cell acute lymphoblastic leukemia (T-ALL). Translocation t(4;16)(q26;p13) with involves TNFRSF17.
== Function ==
[https://www.uniprot.org/uniprot/IL2_HUMAN IL2_HUMAN] Produced by T-cells in response to antigenic or mitogenic stimulation, this protein is required for T-cell proliferation and other activities crucial to regulation of the immune response. Can stimulate B-cells, monocytes, lymphokine-activated killer cells, natural killer cells, and glioma cells.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The immunostimulatory cytokine interleukin-2 (IL-2) is a growth factor for a wide range of leukocytes, including T cells and natural killer (NK) cells. Considerable effort has been invested in using IL-2 as a therapeutic agent for a variety of immune disorders ranging from AIDS to cancer. However, adverse effects have limited its use in the clinic. On activated T cells, IL-2 signals through a quaternary 'high affinity' receptor complex consisting of IL-2, IL-2Ralpha (termed CD25), IL-2Rbeta and IL-2Rgamma. Naive T cells express only a low density of IL-2Rbeta and IL-2Rgamma, and are therefore relatively insensitive to IL-2, but acquire sensitivity after CD25 expression, which captures the cytokine and presents it to IL-2Rbeta and IL-2Rgamma. Here, using in vitro evolution, we eliminated the functional requirement of IL-2 for CD25 expression by engineering an IL-2 'superkine' (also called super-2) with increased binding affinity for IL-2Rbeta. Crystal structures of the IL-2 superkine in free and receptor-bound forms showed that the evolved mutations are principally in the core of the cytokine, and molecular dynamics simulations indicated that the evolved mutations stabilized IL-2, reducing the flexibility of a helix in the IL-2Rbeta binding site, into an optimized receptor-binding conformation resembling that when bound to CD25. The evolved mutations in the IL-2 superkine recapitulated the functional role of CD25 by eliciting potent phosphorylation of STAT5 and vigorous proliferation of T cells irrespective of CD25 expression. Compared to IL-2, the IL-2 superkine induced superior expansion of cytotoxic T cells, leading to improved antitumour responses in vivo, and elicited proportionally less expansion of T regulatory cells and reduced pulmonary oedema. Collectively, we show that in vitro evolution has mimicked the functional role of CD25 in enhancing IL-2 potency and regulating target cell specificity, which has implications for immunotherapy.

Exploiting a natural conformational switch to engineer an interleukin-2 'superkine',Levin AM, Bates DL, Ring AM, Krieg C, Lin JT, Su L, Moraga I, Raeber ME, Bowman GR, Novick P, Pande VS, Fathman CG, Boyman O, Garcia KC Nature. 2012 Mar 25. doi: 10.1038/nature10975. PMID:22446627<ref>PMID:22446627</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 3qaz" style="background-color:#fffaf0;"></div>

==See Also==
*[[Interleukin 3D structures|Interleukin 3D structures]]
*[[Interleukin receptor 3D structures|Interleukin receptor 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Bates DL]]
[[Category: Bowman GR]]
[[Category: Boyman O]]
[[Category: Garcia KC]]
[[Category: Gathman CG]]
[[Category: Khort HE]]
[[Category: Krieg C]]
[[Category: Levin AM]]
[[Category: Lin JT]]
[[Category: Novick P]]
[[Category: Pande VS]]
[[Category: Ring AM]]
[[Category: Su L]]