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Structure paper

TitleStructural basis for IL-12 and IL-23 receptor sharing reveals a gateway for shaping actions on T versus NK cells.
Journal, issue, pagesCell, Vol. 184, Issue 4, Page 983-999.e24, Year 2021
Publish dateFeb 18, 2021
AuthorsCaleb R Glassman / Yamuna Kalyani Mathiharan / Kevin M Jude / Leon Su / Ouliana Panova / Patrick J Lupardus / Jamie B Spangler / Lauren K Ely / Christoph Thomas / Georgios Skiniotis / K Christopher Garcia /
PubMed AbstractInterleukin-12 (IL-12) and IL-23 are heterodimeric cytokines that are produced by antigen-presenting cells to regulate the activation and differentiation of lymphocytes, and they share IL-12Rβ1 as a ...Interleukin-12 (IL-12) and IL-23 are heterodimeric cytokines that are produced by antigen-presenting cells to regulate the activation and differentiation of lymphocytes, and they share IL-12Rβ1 as a receptor signaling subunit. We present a crystal structure of the quaternary IL-23 (IL-23p19/p40)/IL-23R/IL-12Rβ1 complex, together with cryoelectron microscopy (cryo-EM) maps of the complete IL-12 (IL-12p35/p40)/IL-12Rβ2/IL-12Rβ1 and IL-23 receptor (IL-23R) complexes, which reveal "non-canonical" topologies where IL-12Rβ1 directly engages the common p40 subunit. We targeted the shared IL-12Rβ1/p40 interface to design a panel of IL-12 partial agonists that preserved interferon gamma (IFNγ) induction by CD8 T cells but impaired cytokine production from natural killer (NK) cells in vitro. These cell-biased properties were recapitulated in vivo, where IL-12 partial agonists elicited anti-tumor immunity to MC-38 murine adenocarcinoma absent the NK-cell-mediated toxicity seen with wild-type IL-12. Thus, the structural mechanism of receptor sharing used by IL-12 family cytokines provides a protein interface blueprint for tuning this cytokine axis for therapeutics.
External linksCell / PubMed:33606986 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution2.01 - 10.0 Å
Structure data

EMDB-21645:
IL-12 receptor complex
Method: EM (single particle) / Resolution: 10.0 Å

EMDB-21646:
IL-23 receptor complex
Method: EM (single particle) / Resolution: 8.0 Å

PDB-6wdp:
Interleukin 12 receptor subunit beta-1
Method: X-RAY DIFFRACTION / Resolution: 2.01 Å

PDB-6wdq:
IL23/IL23R/IL12Rb1 signaling complex
Method: X-RAY DIFFRACTION / Resolution: 3.4 Å

Chemicals

ChemComp-GOL:
GLYCEROL / Glycerol

ChemComp-SO4:
SULFATE ION / Sulfate

ChemComp-HOH:
WATER / Water

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

Source
  • homo sapiens (human)
KeywordsSIGNALING PROTEIN / cytokine receptor

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