8XRP

The Cryo-EM structure of IL-12, receptor subunit beta-1 and receptor subunit beta-2 complex

Summary for 8XRP

• Entry DOI: 10.2210/pdb8xrp/pdb
• EMDB information: 38609
• Descriptor: Interleukin-12 subunit alpha, Interleukin-12 subunit beta, Interleukin-12 receptor subunit beta-2, ... (6 entities in total)
• Functional Keywords: il-12, il-12rb1, il-12rb2, receptor complex, cytokine
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 16
• Total formula weight: 476826.49

Authors

Chen, H.Q.,Wang, X.Q.,Ge, X.F.,Zeng, J.W.,Wang, J.W. (deposition date: 2024-01-07, release date: 2024-07-24, Last modification date: 2024-11-06)

Primary citation

Chen, H.,Ge, X.,Li, C.,Zeng, J.,Wang, X.
Structure and assembly of the human IL-12 signaling complex.
Structure, 32:1640-, 2024

PubMed Abstract: Interleukin (IL)-12 is a heterodimeric pro-inflammatory cytokine. Our cryoelectron microscopy structure determination of human IL-12 in complex with IL-12Rβ1 and IL-12Rβ2 at a resolution of 3.75 Å reveals that IL-12Rβ2 primarily interacts with the IL-12p35 subunit via its N-terminal Ig-like domain, while IL-12Rβ1 binds to the p40 subunit with its N-terminal fibronectin III domain. This binding mode of IL-12 with its receptors is similar to that of IL-23 but shows notable differences with other cytokines. Through structural information and biochemical assays, we identified Y62, Y189, and K192 as key residues in IL-12p35, which bind to IL-12Rβ2 with high affinity and mediate IL-12 signal transduction. Furthermore, structural comparisons reveal two distinctive conformational states and structural plasticity of the heterodimeric interface in IL-12. As a result, our study advances our understanding of IL-12 signal initiation and opens up new opportunities for the engineering and therapeutic targeting of IL-12.

PubMed: 39111304
DOI: 10.1016/j.str.2024.07.010

Experimental method

ELECTRON MICROSCOPY (3.75 Å)