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.
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Cryo-EM maps and accompanying structural models were deposited in the EMDB/PDB with the following accession codes: EMD-16820/8odz (predimerized mIL-12 cytokine-receptor complex, Class 1), EMD-16821/8oe0 (predimerized mIL-12 cytokine-receptor complex, Class 2), EMD-16824/8oe4 (predimerized hIL-23 cytokine-receptor complex) and EMD-17580/8pb1 (local refinement of predimerized mIL-12 cytokine-receptor complex, Class 1). Cryo-EM maps of the nonpredimerized mIL-12 cytokine–receptor complexes (Class 1 and Class 2) were deposited in the EMDB with codes EMD-16822 and EMD-16823, respectively. Crystallographic coordinates and structure factors were deposited to the PDB with the following accession codes: 8cr6 (mIL-12), 8cr5 (mIL-12BC197S–IL-12Rβ1D1–D2 complex), 8cr8 (hIL-23), 8c7m (hIL-12Rβ1D3–D5:Fab4CrystalKappa complex) and 8odx (hIL-12Rβ1D3–D5:Fab4:anti-Kappa-VHH complex). Structures used for structural comparisons/analyses have the following accession codes: 1f45, 3hmx, 3duh, 3d85, 3d87, 3qwr, 4grw, 5mj3, 5mj4, 5mxa, 5mzv, 5njd, 6uib, 6wdq, 6sff, 6smc, 6sp3, 7pur and 7r3n. Source data are provided with this paper.
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Acknowledgements
We thank the staff of beamlines Proxima1 and Proxima2A (SOLEIL synchrotron, Gif-sur-Yvette, France) and P13 and P14 (PETRA III, Hamburg, Germany) for beamtime allocation and technical support. We thank M. Fislage at the VIB-VUB facility for Biological Electron Cryogenic Microscopy for assistance in data collection, technical support and infrastructural access. The high-performance computing resources and services used in this work were provided by the VSC (Flemish Supercomputer Center), funded by the Research Foundation Flanders (FWO) and the Flemish Government. Y.B. was a post-doctoral research fellow supported by the Research Foundation Flanders (FWO grant no. 12S0519N). S.N.S. acknowledges research support from the FWO (grant no. G0B4918N) and the Flanders Institute for Biotechnology (VIB).
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Y.B., J.F. and R.M. designed and performed recombinant protein production with contributions from M.P., R.A.S. and E.L. J.F. and Y.B. performed cryo-EM grid preparation, data collection, processing, model building and refinement. Y.B., R.M., E.L. and S.N.S. performed X-ray crystallographic data collection. Y.B., J.F., R.M. and E.L. performed X-ray crystallographic data processing, model building and refinement with contributions from S.N.S. J.F. and R.A.S. performed BLI binding studies. M.P. and Y.B. performed IL-23 reporter cellular assays. A.R.M. and R.D.B. performed MD simulations. Y.B., J.F. and S.N.S. analyzed data with contributions from A.R.M. and R.D.B. J.F., Y.B. and S.N.S. wrote the manuscript with contributions from all authors. S.N.S. conceived and supervised the project.
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Extended data
Extended Data Fig. 1 Characterization of the interaction between mouse IL-12 and its cognate receptors via Bio-Layer Interferometry (BLI).
a & b, BLI measurements of the interaction between biotinylated mIL-12, couped on streptavidin (SA) biosensors, and mIL-12Rβ1D1-D2 (a) or biotinylated mIL-12Rβ2D1-D6 and mIL-12 (b). Schematic representations of the interactions are shown above each set of measurements. Measured response curves are shown in blue and fitted curves (using a 1:1 binding model) are shown in red. Used concentrations of analyte are annotated above each individual response curve. KD = Equilibrium dissociation constant. All BLI experiments were performed in triplicate (see Source Data file), and one representative experiment is shown. Displayed KD values are the calculated average of triplicate experiments. c, Multiple sequence alignment of domain 1 (D1) of wild-type hIL-12Rβ1, affinity maturated hIL-12Rβ115 and wild-type mIL-12Rβ1. The location of mutated residues in affinity maturated hIL-12Rβ1 is annotated with a red arrow. Sequence alignment was performed using Clustal Omega57.
Extended Data Fig. 2 CryoEM data processing workflow for the predimerized mIL-12:mIL-12Rβ1D1-D5-DAPK1302-330:mIL-12Rβ2D1-D6-CaM complex.
Data processing was performed in CryoSPARC v3.3.228,29, and map post-processing was performed using DeepEMhancer25. Gold-standard Fourier Shell Correlation (FSC) curves are shown after applying either no mask (blue), a loose mask (green), or a tight mask (red) to both half maps before calculating the FSC. The corrected FSC (purple) is calculated using the tight mask with correction by noise substitution58. The estimated resolution at FSC = 0.143 (dotted purple lines) is shown for the corrected FSC curves (purple lines).
Extended Data Fig. 3 CryoEM data processing workflow for the predimerized hIL-23:hIL-12Rβ1D1-D5-DAPK1302-330:hIL-23R-CaM complex.
Data processing was performed in CryoSPARC v3.3.228,29, and map post-processing was performed using DeepEMhancer25. Gold-standard Fourier Shell Correlation (FSC) curves are shown after applying either no mask (blue), a loose mask (green), or a tight mask (red) to both half maps before calculating the FSC. The corrected FSC (purple) is calculated using the tight mask with correction by noise substitution58. The estimated resolution at FSC = 0.143 (dotted purple lines) is shown for the corrected FSC curves (purple lines).
Extended Data Fig. 4 Gold-standard Fourier Shell Correlation (FSC) curves, local resolution estimation and 3D-FSC analysis of reported maps.
a–c, Gold-standard FSC curves for Class 1 & 2 (a) of the predimerized mIL-12–IL-12Rβ1D1-D5-DAPK1302-330–IL-12Rβ2D1-D6-CaM complex, the predimerized hIL-23–IL-12Rβ1D1-D5-DAPK1302-330–IL-23R-CaM complex (b), and Class 1 & 2 (c) of the non-predimerized mIL-12–IL-12Rβ1D1-D5-Strep-II–IL-12Rβ2D1-D6-Strep-II complex. FSC curves are calculated after applying either no mask (blue), a loose mask (green), or a tight mask (red) to both half maps. The corrected FSC (purple) is calculated using the tight mask with correction by noise substitution58. The estimated resolution at FSC = 0.143 (dotted purple lines) is shown for the corrected FSC curves (purple lines). Map-to-model FSC curves are shown in grey, along with the estimated resolution at FSC = 0.5 (dotted grey lines). To the right of each set of FSC curves, a local resolution coloring of the corresponding 3D reconstruction is displayed, along with 3D-FSC plots calculated using the Remote 3D-FSC Processing Server59 and particle orientation distribution plots generated using an adapted script from cryoEF v1.1.060.
Extended Data Fig. 5 Experimentally observed flexibility in the IL-12 and IL-23 protein complexes.
a, Structural superposition of IL-12 (5 observations) using p40D2D3 as a reference showing inter domain flexibility. mIL-12Rβ1D1-D5 bound structures display a preferred orientation of the p40D1 especially with regards to the p40D1βA-βB and βE-βF loops which are part of the interface. The p35 subunit is also twisted away from p40 upon mIL-12Rβ2 binding. b, Structural superposition of mIL-12Rβ2 (2 structures) using p35 as a reference displays flexibility beyond the p35: mIL-12Rβ2D1 interface. c, structural superposition of hIL-23 (21 observations total) using the p19 helices as a reference showing inter domain flexibility. IL-23R bound structures display an α-helical to 310-helical switch at the N-terminal tip of the D-helix which is the interface hotspot. d, structural superposition of hIL-23 (21 observations of hIL-23 and 1 hp40 only) using the p40D2D3 as a reference showing inter domain flexibility. hIL-12Rβ1 bound structures display a preferred orientation of the p40D1 especially with regards to the p40D1βA-βB and βE-βF loops which are part of the interface. e,f, Structural superpositions of hIL-23R using hIL-23RD1 as reference (e) and human and mouse IL-12Rβ1 using IL-12Rβ1D1 as a reference (f) display flexibility in the receptor domains a well as in cytokine binding. Models utilized in figures are PDB IDs: 1f45, 3hmx, 3duh, 3d85, 3d87, 3qwr, 4grw, 5mj3, 5mj4, 5mxa, 5mzv, 5njd, 6uib, 6wdq, 6sff, 6smc, 6sp3, 7pur, 7r3n, 8odz, 8oe0, 8oe4, 8cr6, 8cr5, 8cr8, 8c7m, 8odx.
Extended Data Fig. 6 Molecular Dynamics (MD) simulations of unbound mouse IL-12, human IL-12 and human IL-23.
Structures of mouse IL-12 (a), human IL-12 (b) and human IL-23 (c), averaged over three replicate 300 ns MD runs, are shown as cartoons colored according to the average root mean square fluctuations (r.m.s.f.) of backbone atom positions over the combined MD trajectory. The thickness of the cartoon loop radius corresponds to the local r.m.s.f. value.
Extended Data Fig. 7 Local refinement strategy and gold-standard Fourier Shell Correlation (FSC) curves, local resolution estimation and 3D-FSC analysis of the local refinement map.
a, Local refinement strategy, using a soft mask around mIL-12 in complex with the first two domains of mIL-12Rβ1 and mIL-12Rβ2, depicted in transparent blue. A map sharpened using a B-factor of −30 Å2 (middle map, colored gray) was used for model real-space refinement, while manual model building was guided by a deepEMhancer sharpened map (right map, colored green, cyan, purple and blue for mIL-12A (p40), mIL-12B (p40), mIL-12Rβ1D1-D2 and mIL-12Rβ2D1-D2 respectively). b, Gold-standard FSC curve of the local refinement map. FSC curves are calculated after applying either no mask (blue), a loose mask (green), or a tight mask (red) to both half maps. The corrected FSC (purple) is calculated using the tight mask with correction by noise substitution58. The estimated resolution at FSC = 0.143 (dotted purple line) is shown for the corrected FSC curve (purple line). A map-to-model FSC curve is shown in grey, along with the estimated resolution at FSC = 0.5 (dotted grey line). To the right of the FSC curves, a local resolution coloring of the local refinement 3D reconstruction is displayed, along with a 3D-FSC plot calculated using the Remote 3D-FSC Processing Server59 and a particle orientation distribution plot generated using an adapted script from cryoEF v1.1.060. c-d, Zooms of the mIL-12A (p35) – mIL-12Rβ2 (c) and mIL-12B (p40) – mIL-12Rβ1 (d) interfaces. Atomic models are displayed as cartoons fitted in the local refinement 3D map displayed as a grey mesh. mIL-12A (p40), mIL-12B (p40), mIL-12Rβ1D1 and mIL-12Rβ2D1 are shown in green, cyan, purple and blue respectively. Hotspot residues in mIL12A (p35) and mIL12B (p40) as identified by Esch et al.18 and Georgy et al.61 are indicated using a red asterisk.
Extended Data Fig. 8 Pairwise sequence alignments of human and mouse IL-12A, IL-23A and IL-12B.
Sequence alignments are shown between human and mouse orthologs of IL-12A (a), IL23A (b) and IL-12B (c). Secretion signals are indicated with a black line, and secondary structure elements are indicated with helices and arrows for α-helices and β-strands respectively. Residues involved in specific interaction interfaces are annotated using colored dots, and N-linked glycosylation sites are annotated using a star. Pairwise alignments were performed using MAFFT62, and ESPript63 was used for display.
Extended Data Fig. 9 Details of the IL-12Rβ1D3-D5:Fab4 interaction.
a, Cartoon representation of the IL-12Rβ1D3-D5:Fab4 interaction. Receptor fragment in cartoon representation and Fab4 chain in surface representation. b, Detailed view of the IL-12Rβ1D3-D5:Fab4 interaction around residue R299 including some waters (red spheres) which are part of the interface. c, Dose-response curve of a SEAP based IL-23 reporter cellular assay in presence or absence of Fab4. EC50 values are reported together with their 95% confidence interval. 3 biological replicates, each in triplicate are shown. d, Cartoon representation of the crystal packing interaction of the better defined (lower B-factor) Fab4 copy interacting with two crystallographic copies (IL-12Rβ1 fragment and other complex not shown). e, The engineered Crystal Kappa mutation (magenta) near the C-terminus of the Light chain (wheat) forms an anti-parallel beta-sheet with the C-terminal beta strand of the Heavy chain (orange) of the neighboring Fab fragment allowing for a crystal lattice.
Supplementary information
Supplementary Information
Supplementary Figs. 1–4, Table 1 and references.
Supplementary Data 1
Source data for MALLS and mass photometry experiments shown in Supplementary Fig. 1.
Source data
Source Data Extended Data Fig./Table 1
Source data for BLI experiments shown in Extended Data Fig. 1.
Source Data Extended Data Fig./Table 9
Source data for IL-23 reporter cellular assays shown in Extended Data Fig. 9.
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Bloch, Y., Felix, J., Merceron, R. et al. Structures of complete extracellular receptor assemblies mediated by IL-12 and IL-23. Nat Struct Mol Biol 31, 591–597 (2024). https://doi.org/10.1038/s41594-023-01190-6
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DOI: https://doi.org/10.1038/s41594-023-01190-6
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