View source for 8oe0


==Cryo-EM structure of a pre-dimerized murine IL-12 complete extracellular signaling complex (Class 2).==
<StructureSection load='8oe0' size='340' side='right'caption='[[8oe0]], [[Resolution|resolution]] 4.60&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8oe0]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8OE0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8OE0 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 4.6&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <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=8oe0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8oe0 OCA], [https://pdbe.org/8oe0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8oe0 RCSB], [https://www.ebi.ac.uk/pdbsum/8oe0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8oe0 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/IL12A_MOUSE IL12A_MOUSE] Heterodimerizes with IL12B to form the IL-12 cytokine or with EBI3/IL27B to form the IL-35 cytokine. IL-12 is primarily produced by professional antigen-presenting cells (APCs) such as B-cells and dendritic cells (DCs) as well as macrophages and granulocytes and regulates T-cell and natural killer-cell responses, induces the production of interferon-gamma (IFN-gamma), favors the differentiation of T-helper 1 (Th1) cells and is an important link between innate resistance and adaptive immunity (PubMed:8766560). Mechanistically, exerts its biological effects through a receptor composed of IL12R1 and IL12R2 subunits. Binding to the receptor results in the rapid tyrosine phosphorylation of a number of cellular substrates including the JAK family kinases TYK2 and JAK2. In turn, recruited STAT4 gets phosphorylated and translocates to the nucleus where it regulates cytokine/growth factor responsive genes (By similarity). As part of IL-35, plays essential roles in maintaining the immune homeostasis of the liver microenvironment and functions also as an immune-suppressive cytokine (PubMed:18033300, PubMed:30197594). Mediates biological events through unconventional receptors composed of IL12RB2 and gp130/IL6ST heterodimers or homodimers. Signaling requires the transcription factors STAT1 and STAT4, which form a unique heterodimer that binds to distinct DNA sites (By similarity).[UniProtKB:P29459]<ref>PMID:18033300</ref> <ref>PMID:30197594</ref> <ref>PMID:8766560</ref> 
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== Publication Abstract from PubMed ==
Cell-surface receptor complexes mediated by pro-inflammatory interleukin (IL)-12 and IL-23, both validated therapeutic targets, are incompletely understood due to the lack of structural insights into their complete extracellular assemblies. Furthermore, there is a paucity of structural details describing the IL-12-receptor interaction interfaces, in contrast to IL-23-receptor complexes. Here we report structures of fully assembled mouse IL-12/human IL-23-receptor complexes comprising the complete extracellular segments of the cognate receptors determined by electron cryo-microscopy. The structures reveal key commonalities but also surprisingly diverse features. Most notably, whereas IL-12 and IL-23 both utilize a conspicuously presented aromatic residue on their alpha-subunit as a hotspot to interact with the N-terminal Ig domain of their high-affinity receptors, only IL-12 juxtaposes receptor domains proximal to the cell membrane. Collectively, our findings will help to complete our understanding of cytokine-mediated assemblies of tall cytokine receptors and will enable a cytokine-specific interrogation of IL-12/IL-23 signaling in physiology and disease.

Structures of complete extracellular receptor assemblies mediated by IL-12 and IL-23.,Bloch Y, Felix J, Merceron R, Provost M, Symakani RA, De Backer R, Lambert E, Mehdipour AR, Savvides SN Nat Struct Mol Biol. 2024 Apr;31(4):591-597. doi: 10.1038/s41594-023-01190-6. , Epub 2024 Jan 29. PMID:38287195<ref>PMID:38287195</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 8oe0" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Mus musculus]]
[[Category: Bloch Y]]
[[Category: Felix J]]
[[Category: Savvides SN]]