4grw

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

Structural highlights

4grw is a 10 chain structure with sequence from Homo sapiens and Lama glama. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.55Å
Ligands:BMA, MAN, NAG
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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.[1] [2] [3]

Publication Abstract from PubMed

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.

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[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Citations
6 reviews cite this structure
Nanobodies: Next Generation of Cancer Diagnostics and Therapeutics.
Yang et al. (2020)
5 more
15 other articles
No citations found

See Also

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ 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
  4. ↑ Desmyter A, Spinelli S, Boutton C, Saunders M, Blachetot C, de Haard H, Denecker G, Van Roy M, Cambillau C, Rommelaere H. Neutralization of Human Interleukin 23 by Multivalent Nanobodies Explained by the Structure of Cytokine-Nanobody Complex. Front Immunol. 2017 Aug 21;8:884. doi: 10.3389/fimmu.2017.00884. eCollection, 2017. PMID:28871249 doi:http://dx.doi.org/10.3389/fimmu.2017.00884

Contents


PDB ID 4grw

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OCA

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