8C7M

Interleukin 12 receptor subunit beta-1 Fn domains in complex with antagonistic FAb fragment.

Summary for 8C7M

• Entry DOI: 10.2210/pdb8c7m/pdb
• Descriptor: Interleukin-12 receptor subunit beta-1, FAb4 Heavy chain, FAb4 Crystal Kappa Light chain, ... (6 entities in total)
• Functional Keywords: receptor, antagonist, antibody, cytokine
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 165742.31

Authors

Bloch, Y.,Savvides, S.N. (deposition date: 2023-01-16, release date: 2024-01-31, Last modification date: 2024-10-09)

Primary citation

Bloch, Y.,Felix, J.,Merceron, R.,Provost, M.,Symakani, R.A.,De Backer, R.,Lambert, E.,Mehdipour, A.R.,Savvides, S.N.
Structures of complete extracellular receptor assemblies mediated by IL-12 and IL-23.
Nat.Struct.Mol.Biol., 31:591-597, 2024

PubMed Abstract: Cell-surface receptor complexes mediated by pro-inflammatory interleukin (IL)-12 and IL-23, both validated therapeutic targets, are incompletely understood due to the lack of structural insights into their complete extracellular assemblies. Furthermore, there is a paucity of structural details describing the IL-12-receptor interaction interfaces, in contrast to IL-23-receptor complexes. Here we report structures of fully assembled mouse IL-12/human IL-23-receptor complexes comprising the complete extracellular segments of the cognate receptors determined by electron cryo-microscopy. The structures reveal key commonalities but also surprisingly diverse features. Most notably, whereas IL-12 and IL-23 both utilize a conspicuously presented aromatic residue on their α-subunit as a hotspot to interact with the N-terminal Ig domain of their high-affinity receptors, only IL-12 juxtaposes receptor domains proximal to the cell membrane. Collectively, our findings will help to complete our understanding of cytokine-mediated assemblies of tall cytokine receptors and will enable a cytokine-specific interrogation of IL-12/IL-23 signaling in physiology and disease.

PubMed: 38287195
DOI: 10.1038/s41594-023-01190-6

Experimental method

X-RAY DIFFRACTION (2.56 Å)