+Search query
-Structure paper
Title | Structural basis for IL-12 and IL-23 receptor sharing reveals a gateway for shaping actions on T versus NK cells. |
---|---|
Journal, issue, pages | Cell, Vol. 184, Issue 4, Page 983-999.e24, Year 2021 |
Publish date | Feb 18, 2021 |
![]() | Caleb 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 Abstract | 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 ...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. |
![]() | ![]() ![]() ![]() |
Methods | EM (single particle) / X-ray diffraction |
Resolution | 2.01 - 10.0 Å |
Structure data | ![]() EMDB-21645: ![]() EMDB-21646: ![]() PDB-6wdp: ![]() PDB-6wdq: |
Chemicals | ![]() ChemComp-GOL: ![]() ChemComp-SO4: ![]() ChemComp-HOH: ![]() ChemComp-NAG: |
Source |
|
![]() | SIGNALING PROTEIN / cytokine receptor |