7zxk

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Human IL-27 in complex with neutralizing SRF388 FAb fragment

Structural highlights

7zxk is a 8 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.2Å
Ligands:NAG
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

IL27B_HUMAN Associates with IL27 to form the IL-27 interleukin, a heterodimeric cytokine which functions in innate immunity. IL-27 has pro- and anti-inflammatory properties, that can regulate T-helper cell development, suppress T-cell proliferation, stimulate cytotoxic T-cell activity, induce isotype switching in B-cells, and that has diverse effects on innate immune cells. Among its target cells are CD4 T-helper cells which can differentiate in type 1 effector cells (TH1), type 2 effector cells (TH2) and IL17 producing helper T-cells (TH17). It drives rapid clonal expansion of naive but not memory CD4 T-cells. It also strongly synergizes with IL-12 to trigger interferon-gamma/IFN-gamma production of naive CD4 T-cells, binds to the cytokine receptor WSX-1/TCCR. Another important role of IL-27 is its antitumor activity as well as its antiangiogenic activity with activation of production of antiangiogenic chemokines.[1]

Publication Abstract from PubMed

Interleukin-27 (IL-27) uniquely assembles p28 and EBI3 subunits to a heterodimeric cytokine that signals via IL-27Ralpha and gp130. To provide the structural framework for receptor activation by IL-27 and its emerging therapeutic targeting, we report here crystal structures of mouse IL-27 in complex with IL-27Ralpha and of human IL-27 in complex with SRF388, a monoclonal antibody undergoing clinical trials with oncology indications. One face of the helical p28 subunit interacts with EBI3, while the opposite face nestles into the interdomain elbow of IL-27Ralpha to juxtapose IL-27Ralpha to EBI3. This orients IL-27Ralpha for paired signaling with gp130, which only uses its immunoglobulin domain to bind to IL-27. Such a signaling complex is distinct from those mediated by IL-12 and IL-23. The SRF388 binding epitope on IL-27 overlaps with the IL-27Ralpha interaction site explaining its potent antagonistic properties. Collectively, our findings will facilitate the mechanistic interrogation, engineering, and therapeutic targeting of IL-27.

Structural basis of activation and antagonism of receptor signaling mediated by interleukin-27.,Skladanowska K, Bloch Y, Strand J, White KF, Hua J, Aldridge D, Welin M, Logan DT, Soete A, Merceron R, Murphy C, Provost M, Bazan JF, Hunter CA, Hill JA, Savvides SN Cell Rep. 2022 Oct 18;41(3):111490. doi: 10.1016/j.celrep.2022.111490. PMID:36261006[2]

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

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Citations
1 reviews cite this structure
IL-27 expression regulation and its effects on adaptive immunity against viruses.
Andres-Martin et al. (2024)
0 more
3 other articles
No citations found

See Also

References

  1. ↑ Pflanz S, Timans JC, Cheung J, Rosales R, Kanzler H, Gilbert J, Hibbert L, Churakova T, Travis M, Vaisberg E, Blumenschein WM, Mattson JD, Wagner JL, To W, Zurawski S, McClanahan TK, Gorman DM, Bazan JF, de Waal Malefyt R, Rennick D, Kastelein RA. IL-27, a heterodimeric cytokine composed of EBI3 and p28 protein, induces proliferation of naive CD4+ T cells. Immunity. 2002 Jun;16(6):779-90. doi: 10.1016/s1074-7613(02)00324-2. PMID:12121660 doi:http://dx.doi.org/10.1016/s1074-7613(02)00324-2
  2. ↑ Skladanowska K, Bloch Y, Strand J, White KF, Hua J, Aldridge D, Welin M, Logan DT, Soete A, Merceron R, Murphy C, Provost M, Bazan JF, Hunter CA, Hill JA, Savvides SN. Structural basis of activation and antagonism of receptor signaling mediated by interleukin-27. Cell Rep. 2022 Oct 18;41(3):111490. doi: 10.1016/j.celrep.2022.111490. PMID:36261006 doi:http://dx.doi.org/10.1016/j.celrep.2022.111490

Contents


PDB ID 7zxk

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