5mxa

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==Structure of unbound Interleukin-23==
==Structure of unbound Interleukin-23==
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<StructureSection load='5mxa' size='340' side='right' caption='[[5mxa]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
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<StructureSection load='5mxa' size='340' side='right'caption='[[5mxa]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[5mxa]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5MXA OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5MXA FirstGlance]. <br>
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<table><tr><td colspan='2'>[[5mxa]] 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=5MXA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5MXA FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.501&#8491;</td></tr>
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<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=5mxa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mxa OCA], [http://pdbe.org/5mxa PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5mxa RCSB], [http://www.ebi.ac.uk/pdbsum/5mxa PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5mxa ProSAT]</span></td></tr>
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<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=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5mxa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mxa OCA], [https://pdbe.org/5mxa PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5mxa RCSB], [https://www.ebi.ac.uk/pdbsum/5mxa PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5mxa ProSAT]</span></td></tr>
</table>
</table>
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== Disease ==
 
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[[http://www.uniprot.org/uniprot/IL12B_HUMAN IL12B_HUMAN]] Defects in IL12B are a cause of Mendelian susceptibility to mycobacterial disease (MSMD) [MIM:[http://omim.org/entry/209950 209950]]; also known as familial disseminated atypical mycobacterial infection. This rare condition confers predisposition to illness caused by moderately virulent mycobacterial species, such as Bacillus Calmette-Guerin (BCG) vaccine and environmental non-tuberculous mycobacteria, and by the more virulent Mycobacterium tuberculosis. Other microorganisms rarely cause severe clinical disease in individuals with susceptibility to mycobacterial infections, with the exception of Salmonella which infects less than 50% of these individuals. The pathogenic mechanism underlying MSMD is the impairment of interferon-gamma mediated immunity, whose severity determines the clinical outcome. Some patients die of overwhelming mycobacterial disease with lepromatous-like lesions in early childhood, whereas others develop, later in life, disseminated but curable infections with tuberculoid granulomas. MSMD is a genetically heterogeneous disease with autosomal recessive, autosomal dominant or X-linked inheritance.<ref>PMID:9854038</ref> <ref>PMID:11753820</ref> Genetic variations in IL12B are a cause of susceptibility to psoriasis type 11 (PSORS11) [MIM:[http://omim.org/entry/612599 612599]]. Psoriasis is a common, chronic inflammatory disease of the skin with multifactorial etiology. It is characterized by red, scaly plaques usually found on the scalp, elbows and knees. These lesions are caused by abnormal keratinocyte proliferation and infiltration of inflammatory cells into the dermis and epidermis.<ref>PMID:9854038</ref> <ref>PMID:11753820</ref>
 
== Function ==
== Function ==
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[[http://www.uniprot.org/uniprot/IL23A_HUMAN IL23A_HUMAN]] Associates with IL12B to form the IL-23 interleukin, a heterodimeric cytokine which functions in innate and adaptive immunity. IL-23 may constitute with IL-17 an acute response to infection in peripheral tissues. IL-23 binds to a heterodimeric receptor complex composed of IL12RB1 and IL23R, activates the Jak-Stat signaling cascade, stimulates memory rather than naive T-cells and promotes production of proinflammatory cytokines. IL-23 induces autoimmune inflammation and thus may be responsible for autoimmune inflammatory diseases and may be important for tumorigenesis.<ref>PMID:11114383</ref> <ref>PMID:12023369</ref> <ref>PMID:16424222</ref> [[http://www.uniprot.org/uniprot/IL12B_HUMAN IL12B_HUMAN]] Cytokine that can act as a growth factor for activated T and NK cells, enhance the lytic activity of NK/lymphokine-activated killer cells, and stimulate the production of IFN-gamma by resting PBMC.<ref>PMID:11114383</ref> Associates with IL23A to form the IL-23 interleukin, a heterodimeric cytokine which functions in innate and adaptive immunity. IL-23 may constitute with IL-17 an acute response to infection in peripheral tissues. IL-23 binds to a heterodimeric receptor complex composed of IL12RB1 and IL23R, activates the Jak-Stat signaling cascade, stimulates memory rather than naive T-cells and promotes production of proinflammatory cytokines. IL-23 induces autoimmune inflammation and thus may be responsible for autoimmune inflammatory diseases and may be important for tumorigenesis.<ref>PMID:11114383</ref>
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[https://www.uniprot.org/uniprot/IL23A_HUMAN IL23A_HUMAN] Associates with IL12B to form the IL-23 interleukin, a heterodimeric cytokine which functions in innate and adaptive immunity. IL-23 may constitute with IL-17 an acute response to infection in peripheral tissues. IL-23 binds to a heterodimeric receptor complex composed of IL12RB1 and IL23R, activates the Jak-Stat signaling cascade, stimulates memory rather than naive T-cells and promotes production of proinflammatory cytokines. IL-23 induces autoimmune inflammation and thus may be responsible for autoimmune inflammatory diseases and may be important for tumorigenesis.<ref>PMID:11114383</ref> <ref>PMID:12023369</ref> <ref>PMID:16424222</ref>
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<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
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Interleukin-23 (IL-23), a member of the IL-12 family, is a heterodimeric cytokine composed of p19 and p40 subunits. IL-23 plays crucial roles in the activation, proliferation and survival of IL-17-producing helper T cells which induce various autoimmune diseases. Human p19 and p40 subunits were cloned and coexpressed in N-acetylglucosaminyltransferase I-negative 293S cells, which produce high-mannose-type glycosylated proteins in order to diminish the heterogeneity of modified N-linked glycans. The glycosylated human IL-23 was purified and crystallized by the hanging-drop vapour-diffusion method. X-ray diffraction data were then collected to 2.6 A resolution. The crystal belonged to space group P6(1) or P6(5), with unit-cell parameters a = b = 108.94, c = 83.79 A, gamma = 120 degrees . Assuming that the crystal contains one molecule per asymmetric unit, the calculated Matthews coefficient was 2.69 A(3) Da(-1), with a solvent content of 54.2%. The structure was determined by the molecular-replacement method, with an initial R factor of 52.6%. After subsequent rigid-body and positional refinement, the R(work) and R(free) values decreased to 31.4% and 38.7%, respectively.
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Interleukin-23 (IL-23), an IL-12 family cytokine, plays pivotal roles in pro-inflammatory T helper 17 cell responses linked to autoimmune and inflammatory diseases. Despite intense therapeutic targeting, structural and mechanistic insights into receptor complexes mediated by IL-23, and by IL-12 family members in general, have remained elusive. We determined a crystal structure of human IL-23 in complex with its cognate receptor, IL-23R, and revealed that IL-23R bound to IL-23 exclusively via its N-terminal immunoglobulin domain. The structural and functional hotspot of this interaction partially restructured the helical IL-23p19 subunit of IL-23 and restrained its IL-12p40 subunit to cooperatively bind the shared receptor IL-12Rbeta1 with high affinity. Together with structural insights from the interaction of IL-23 with the inhibitory antibody briakinumab and by leveraging additional IL-23:antibody complexes, we propose a mechanistic paradigm for IL-23 and IL-12 whereby cognate receptor binding to the helical cytokine subunits primes recruitment of the shared receptors via the IL-12p40 subunit.
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Preparation, crystallization and preliminary X-ray diffraction studies of the glycosylated form of human interleukin-23.,Shirouzono T, Chirifu M, Nakamura C, Yamagata Y, Ikemizu S Acta Crystallogr Sect F Struct Biol Cryst Commun. 2012 Apr 1;68(Pt 4):432-5. doi:, 10.1107/S1744309112005295. Epub 2012 Mar 27. PMID:22505413<ref>PMID:22505413</ref>
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Structural Activation of Pro-inflammatory Human Cytokine IL-23 by Cognate IL-23 Receptor Enables Recruitment of the Shared Receptor IL-12Rbeta1.,Bloch Y, Bouchareychas L, Merceron R, Skladanowska K, Van den Bossche L, Detry S, Govindarajan S, Elewaut D, Haerynck F, Dullaers M, Adamopoulos IE, Savvides SN Immunity. 2017 Dec 21. pii: S1074-7613(17)30537-X. doi:, 10.1016/j.immuni.2017.12.008. PMID:29287995<ref>PMID:29287995</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
<div class="pdbe-citations 5mxa" style="background-color:#fffaf0;"></div>
<div class="pdbe-citations 5mxa" style="background-color:#fffaf0;"></div>
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==See Also==
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*[[Interleukin 3D structures|Interleukin 3D structures]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Bloch, Y]]
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[[Category: Homo sapiens]]
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[[Category: Savvides, S N]]
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[[Category: Large Structures]]
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[[Category: Cytokine]]
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[[Category: Bloch Y]]
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[[Category: Extracellular]]
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[[Category: Savvides SN]]
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[[Category: Fibronectin type iii]]
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[[Category: Inflammation]]
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Current revision

Structure of unbound Interleukin-23

PDB ID 5mxa

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