| Structural highlights
3d85 is a 4 chain structure with sequence from Human and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , |
| Related: | 1f45, 3d87 |
| Gene: | IL23A, SGRF, UNQ2498/PRO5798 (HUMAN), IL12B, NKSF2 (HUMAN) |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
[IL12B_HUMAN] Defects in IL12B are a cause of Mendelian susceptibility to mycobacterial disease (MSMD) [MIM: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.[1] [2] Genetic variations in IL12B are a cause of susceptibility to psoriasis type 11 (PSORS11) [MIM: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.[3] [4]
Function
[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.[5] 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.[6] [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.[7] [8] [9]
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 (IL)-23 is a pro-inflammatory cytokine playing a key role in the pathogenesis of several autoimmune and inflammatory diseases. We have determined the crystal structures of the heterodimeric p19-p40 IL-23 and its complex with the Fab (antigen-binding fragment) of a neutralizing antibody at 2.9 and 1.9 A, respectively. The IL-23 structure closely resembles that of IL-12. They share the common p40 subunit, and IL-23 p19 overlaps well with IL-12 p35. Along the hydrophilic heterodimeric interface, fewer charged residues are involved for IL-23 compared with IL-12. The binding site of the Fab is located exclusively on the p19 subunit, and comparison with published cytokine-receptor structures suggests that it overlaps with the IL-23 receptor binding site.
Crystal structures of the pro-inflammatory cytokine interleukin-23 and its complex with a high-affinity neutralizing antibody.,Beyer BM, Ingram R, Ramanathan L, Reichert P, Le HV, Madison V, Orth P J Mol Biol. 2008 Oct 17;382(4):942-55. Epub 2008 Aug 7. PMID:18708069[10]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Altare F, Lammas D, Revy P, Jouanguy E, Doffinger R, Lamhamedi S, Drysdale P, Scheel-Toellner D, Girdlestone J, Darbyshire P, Wadhwa M, Dockrell H, Salmon M, Fischer A, Durandy A, Casanova JL, Kumararatne DS. Inherited interleukin 12 deficiency in a child with bacille Calmette-Guerin and Salmonella enteritidis disseminated infection. J Clin Invest. 1998 Dec 15;102(12):2035-40. PMID:9854038 doi:10.1172/JCI4950
- ↑ Picard C, Fieschi C, Altare F, Al-Jumaah S, Al-Hajjar S, Feinberg J, Dupuis S, Soudais C, Al-Mohsen IZ, Genin E, Lammas D, Kumararatne DS, Leclerc T, Rafii A, Frayha H, Murugasu B, Wah LB, Sinniah R, Loubser M, Okamoto E, Al-Ghonaium A, Tufenkeji H, Abel L, Casanova JL. Inherited interleukin-12 deficiency: IL12B genotype and clinical phenotype of 13 patients from six kindreds. Am J Hum Genet. 2002 Feb;70(2):336-48. Epub 2001 Dec 17. PMID:11753820 doi:S0002-9297(07)63949-4
- ↑ Altare F, Lammas D, Revy P, Jouanguy E, Doffinger R, Lamhamedi S, Drysdale P, Scheel-Toellner D, Girdlestone J, Darbyshire P, Wadhwa M, Dockrell H, Salmon M, Fischer A, Durandy A, Casanova JL, Kumararatne DS. Inherited interleukin 12 deficiency in a child with bacille Calmette-Guerin and Salmonella enteritidis disseminated infection. J Clin Invest. 1998 Dec 15;102(12):2035-40. PMID:9854038 doi:10.1172/JCI4950
- ↑ Picard C, Fieschi C, Altare F, Al-Jumaah S, Al-Hajjar S, Feinberg J, Dupuis S, Soudais C, Al-Mohsen IZ, Genin E, Lammas D, Kumararatne DS, Leclerc T, Rafii A, Frayha H, Murugasu B, Wah LB, Sinniah R, Loubser M, Okamoto E, Al-Ghonaium A, Tufenkeji H, Abel L, Casanova JL. Inherited interleukin-12 deficiency: IL12B genotype and clinical phenotype of 13 patients from six kindreds. Am J Hum Genet. 2002 Feb;70(2):336-48. Epub 2001 Dec 17. PMID:11753820 doi:S0002-9297(07)63949-4
- ↑ Oppmann B, Lesley R, Blom B, Timans JC, Xu Y, Hunte B, Vega F, Yu N, Wang J, Singh K, Zonin F, Vaisberg E, Churakova T, Liu M, Gorman D, Wagner J, Zurawski S, Liu Y, Abrams JS, Moore KW, Rennick D, de Waal-Malefyt R, Hannum C, Bazan JF, Kastelein RA. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity. 2000 Nov;13(5):715-25. PMID:11114383
- ↑ Oppmann B, Lesley R, Blom B, Timans JC, Xu Y, Hunte B, Vega F, Yu N, Wang J, Singh K, Zonin F, Vaisberg E, Churakova T, Liu M, Gorman D, Wagner J, Zurawski S, Liu Y, Abrams JS, Moore KW, Rennick D, de Waal-Malefyt R, Hannum C, Bazan JF, Kastelein RA. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity. 2000 Nov;13(5):715-25. PMID:11114383
- ↑ Oppmann B, Lesley R, Blom B, Timans JC, Xu Y, Hunte B, Vega F, Yu N, Wang J, Singh K, Zonin F, Vaisberg E, Churakova T, Liu M, Gorman D, Wagner J, Zurawski S, Liu Y, Abrams JS, Moore KW, Rennick D, de Waal-Malefyt R, Hannum C, Bazan JF, Kastelein RA. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity. 2000 Nov;13(5):715-25. PMID:11114383
- ↑ Parham C, Chirica M, Timans J, Vaisberg E, Travis M, Cheung J, Pflanz S, Zhang R, Singh KP, Vega F, To W, Wagner J, O'Farrell AM, McClanahan T, Zurawski S, Hannum C, Gorman D, Rennick DM, Kastelein RA, de Waal Malefyt R, Moore KW. A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbeta1 and a novel cytokine receptor subunit, IL-23R. J Immunol. 2002 Jun 1;168(11):5699-708. PMID:12023369
- ↑ Piskin G, Sylva-Steenland RM, Bos JD, Teunissen MB. In vitro and in situ expression of IL-23 by keratinocytes in healthy skin and psoriasis lesions: enhanced expression in psoriatic skin. J Immunol. 2006 Feb 1;176(3):1908-15. PMID:16424222
- ↑ Beyer BM, Ingram R, Ramanathan L, Reichert P, Le HV, Madison V, Orth P. Crystal structures of the pro-inflammatory cytokine interleukin-23 and its complex with a high-affinity neutralizing antibody. J Mol Biol. 2008 Oct 17;382(4):942-55. Epub 2008 Aug 7. PMID:18708069 doi:10.1016/j.jmb.2008.08.001
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