6WDQ

IL23/IL23R/IL12Rb1 signaling complex

Summary for 6WDQ

• Entry DOI: 10.2210/pdb6wdq/pdb
• Descriptor: Interleukin-12 subunit beta, Interleukin-23 subunit alpha, Interleukin-23 receptor, ... (8 entities in total)
• Functional Keywords: cytokine receptor, signaling protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 116493.50

Authors

Jude, K.M.,Ely, L.K.,Glassman, C.R.,Thomas, C.,Spangler, J.B.,Lupardus, P.J.,Garcia, K.C. (deposition date: 2020-04-01, release date: 2021-02-24, Last modification date: 2024-10-16)

Primary citation

Glassman, C.R.,Mathiharan, Y.K.,Jude, K.M.,Su, L.,Panova, O.,Lupardus, P.J.,Spangler, J.B.,Ely, L.K.,Thomas, C.,Skiniotis, G.,Garcia, K.C.
Structural basis for IL-12 and IL-23 receptor sharing reveals a gateway for shaping actions on T versus NK cells.
Cell, 184:983-999.e24, 2021

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 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.

PubMed: 33606986
DOI: 10.1016/j.cell.2021.01.018

Experimental method

X-RAY DIFFRACTION (3.4 Å)