4grw

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{{STRUCTURE_4grw| PDB=4grw | SCENE= }}
 
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===Structure of a complex of human IL-23 with 3 Nanobodies (Llama vHHs)===
 
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==Disease==
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==Structure of a complex of human IL-23 with 3 Nanobodies (Llama vHHs)==
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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>
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<StructureSection load='4grw' size='340' side='right'caption='[[4grw]], [[Resolution|resolution]] 2.55&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[4grw]] is a 10 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Lama_glama Lama glama]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4GRW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4GRW FirstGlance]. <br>
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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]] 2.55&#8491;</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=4grw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4grw OCA], [https://pdbe.org/4grw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4grw RCSB], [https://www.ebi.ac.uk/pdbsum/4grw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4grw ProSAT]</span></td></tr>
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</table>
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== Function ==
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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;">
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== Publication Abstract from PubMed ==
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The heterodimeric cytokine interleukin (IL) 23 comprises the IL12-shared p40 subunit and an IL23-specific subunit, p19. Together with IL12 and IL27, IL23 sits at the apex of the regulatory mechanisms shaping adaptive immune responses. IL23, together with IL17, plays an important role in the development of chronic inflammation and autoimmune inflammatory diseases. In this context, we generated monovalent antihuman IL23 variable heavy chain domain of llama heavy chain antibody (VHH) domains (Nanobodies((R))) with low nanomolar affinity for human interleukin (hIL) 23. The crystal structure of a quaternary complex assembling hIL23 and several nanobodies against p19 and p40 subunits allowed identification of distinct epitopes and enabled rational design of a multivalent IL23-specific blocking nanobody. Taking advantage of the ease of nanobody formatting, multivalent IL23 nanobodies were assembled with properly designed linkers flanking an antihuman serum albumin nanobody, with improved hIL23 neutralization capacity in vitro and in vivo, as compared to the monovalent nanobodies. These constructs with long exposure time are excellent candidates for further developments targeting Crohn's disease, rheumatoid arthritis, and psoriasis.
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==Function==
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Neutralization of Human Interleukin 23 by Multivalent Nanobodies Explained by the Structure of Cytokine-Nanobody Complex.,Desmyter A, Spinelli S, Boutton C, Saunders M, Blachetot C, de Haard H, Denecker G, Van Roy M, Cambillau C, Rommelaere H Front Immunol. 2017 Aug 21;8:884. doi: 10.3389/fimmu.2017.00884. eCollection, 2017. PMID:28871249<ref>PMID:28871249</ref>
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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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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[4grw]] is a 10 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4GRW OCA].
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</div>
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<div class="pdbe-citations 4grw" style="background-color:#fffaf0;"></div>
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==Reference==
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==See Also==
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<references group="xtra"/><references/>
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*[[Antibody 3D structures|Antibody 3D structures]]
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[[Category: Button, C.]]
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*[[Interleukin 3D structures|Interleukin 3D structures]]
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[[Category: Cambillau, C.]]
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*[[Transcription initiation factors 3D structures|Transcription initiation factors 3D structures]]
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[[Category: Desmyter, A.]]
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*[[3D structures of non-human antibody|3D structures of non-human antibody]]
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[[Category: Haard, H de.]]
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== References ==
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[[Category: Rommelaere, H.]]
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<references/>
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[[Category: Saunders, M.]]
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__TOC__
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[[Category: Spinelli, S.]]
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</StructureSection>
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[[Category: Union, A.]]
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[[Category: Homo sapiens]]
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[[Category: Cytokine]]
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[[Category: Lama glama]]
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[[Category: Immune system]]
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[[Category: Large Structures]]
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[[Category: Immunoglobulin fold]]
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[[Category: Button C]]
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[[Category: Vhh domain]]
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[[Category: Cambillau C]]
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[[Category: Desmyter A]]
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[[Category: Rommelaere H]]
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[[Category: Saunders M]]
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[[Category: Spinelli S]]
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[[Category: Union A]]
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[[Category: De Haard H]]

Current revision

Structure of a complex of human IL-23 with 3 Nanobodies (Llama vHHs)

PDB ID 4grw

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