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- PDB-8oe4: Cryo-EM structure of a pre-dimerized human IL-23 complete extrace... -
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Open data
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Basic information
Entry | Database: PDB / ID: 8oe4 | |||||||||
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Title | Cryo-EM structure of a pre-dimerized human IL-23 complete extracellular signaling complex. | |||||||||
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![]() | SIGNALING PROTEIN / Complex / Cytokine / Receptor | |||||||||
Function / homology | ![]() late endosome lumen / interleukin-23-mediated signaling pathway / regulation of tyrosine phosphorylation of STAT protein / interleukin-23 receptor binding / interleukin-12 alpha subunit binding / interleukin-12 complex / interleukin-23 complex / natural killer cell activation involved in immune response / positive regulation of natural killer cell activation / positive regulation of lymphocyte proliferation ...late endosome lumen / interleukin-23-mediated signaling pathway / regulation of tyrosine phosphorylation of STAT protein / interleukin-23 receptor binding / interleukin-12 alpha subunit binding / interleukin-12 complex / interleukin-23 complex / natural killer cell activation involved in immune response / positive regulation of natural killer cell activation / positive regulation of lymphocyte proliferation / positive regulation of natural killer cell mediated cytotoxicity directed against tumor cell target / negative regulation of vascular endothelial growth factor signaling pathway / negative regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis / positive regulation of tissue remodeling / cellular response to hydroperoxide / : / tissue remodeling / positive regulation of T-helper 1 type immune response / sexual reproduction / regulation of response to tumor cell / positive regulation of autophagic cell death / DAPK1-calmodulin complex / positive regulation of NK T cell activation / positive regulation of smooth muscle cell apoptotic process / positive regulation of mononuclear cell proliferation / interleukin-12 receptor binding / positive regulation of memory T cell differentiation / interleukin-12 receptor complex / natural killer cell activation / T-helper cell differentiation / interleukin-23 receptor complex / defense response to tumor cell / Interleukin-23 signaling / Caspase activation via Dependence Receptors in the absence of ligand / negative regulation of interleukin-17 production / positive regulation of osteoclast differentiation / positive regulation of T-helper 17 type immune response / positive regulation of NK T cell proliferation / interleukin-12-mediated signaling pathway / positive regulation of T-helper 17 cell lineage commitment / positive regulation of neutrophil chemotaxis / Interleukin-12 signaling / response to UV-B / regulation of NMDA receptor activity / CaM pathway / Cam-PDE 1 activation / positive regulation of natural killer cell proliferation / cytokine receptor activity / positive regulation of granulocyte macrophage colony-stimulating factor production / Sodium/Calcium exchangers / syntaxin-1 binding / Calmodulin induced events / Reduction of cytosolic Ca++ levels / calcium/calmodulin-dependent protein kinase activity / CREB1 phosphorylation through the activation of CaMKII/CaMKK/CaMKIV cascasde / Activation of Ca-permeable Kainate Receptor / Loss of phosphorylation of MECP2 at T308 / CREB1 phosphorylation through the activation of Adenylate Cyclase / PKA activation / negative regulation of high voltage-gated calcium channel activity / CaMK IV-mediated phosphorylation of CREB / Glycogen breakdown (glycogenolysis) / positive regulation of cyclic-nucleotide phosphodiesterase activity / organelle localization by membrane tethering / negative regulation of calcium ion export across plasma membrane / CLEC7A (Dectin-1) induces NFAT activation / mitochondrion-endoplasmic reticulum membrane tethering / autophagosome membrane docking / T-helper 1 type immune response / regulation of cardiac muscle cell action potential / Activation of RAC1 downstream of NMDARs / negative regulation of interleukin-10 production / positive regulation of ryanodine-sensitive calcium-release channel activity / regulation of cell communication by electrical coupling involved in cardiac conduction / Negative regulation of NMDA receptor-mediated neuronal transmission / negative regulation of peptidyl-threonine phosphorylation / Synthesis of IP3 and IP4 in the cytosol / Unblocking of NMDA receptors, glutamate binding and activation / positive regulation of activated T cell proliferation / defense response to protozoan / Phase 0 - rapid depolarisation / response to type II interferon / negative regulation of ryanodine-sensitive calcium-release channel activity / protein phosphatase activator activity / positive regulation of cysteine-type endopeptidase activity involved in apoptotic process / positive regulation of interleukin-17 production / RHO GTPases activate PAKs / Interleukin-10 signaling / cytokine binding / : / Ion transport by P-type ATPases / Long-term potentiation / positive regulation of interleukin-10 production / Uptake and function of anthrax toxins / Regulation of MECP2 expression and activity / Calcineurin activates NFAT / catalytic complex / positive regulation of cell adhesion / DARPP-32 events / detection of calcium ion Similarity search - Function | |||||||||
Biological species | ![]() | |||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.6 Å | |||||||||
![]() | Bloch, Y. / Felix, J. / Savvides, S.N. | |||||||||
Funding support | ![]()
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![]() | ![]() Title: Structures of complete extracellular receptor assemblies mediated by IL-12 and IL-23. Authors: Yehudi Bloch / Jan Felix / Romain Merceron / Mathias Provost / Royan Alipour Symakani / Robin De Backer / Elisabeth Lambert / Ahmad R Mehdipour / Savvas N Savvides / ![]() ![]() ![]() ![]() 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 ...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. | |||||||||
History |
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Structure visualization
Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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Download
PDBx/mmCIF format | ![]() | 241.7 KB | Display | ![]() |
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PDB format | ![]() | 186.6 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Arichive directory | ![]() ![]() | HTTPS FTP |
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-Related structure data
Related structure data | ![]() 16824MC ![]() 8c7mC ![]() 8cr5C ![]() 8cr6C ![]() 8cr8C ![]() 8odxC ![]() 8odzC ![]() 8oe0C ![]() 8pb1C ![]() 8ppmC C: citing same article ( M: map data used to model this data |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
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Assembly
Deposited unit | ![]()
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Components
-Interleukin-12 ... , 2 types, 2 molecules AD
#1: Protein | Mass: 34740.930 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Details: N-glycosylation mutant: Asparagine 303 (N303) is mutated to Aspartic acid (D303). Source: (gene. exp.) ![]() ![]() |
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#4: Protein | Mass: 60187.316 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() References: UniProt: P42701, UniProt: P53355, non-specific serine/threonine protein kinase |
-Interleukin-23 ... , 2 types, 2 molecules BC
#2: Protein | Mass: 20650.117 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() |
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#3: Protein | Mass: 54991.391 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() |
-Sugars , 3 types, 4 molecules ![](data/chem/img/NAG.gif)
#5: Polysaccharide | alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1- ...alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose Source method: isolated from a genetically manipulated source |
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#6: Polysaccharide | 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose Source method: isolated from a genetically manipulated source |
#7: Sugar |
-Details
Has ligand of interest | N |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
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Sample preparation
Component | Name: Human IL-23 in complex with hIL-12Rbeta1-DAPK1 and hIL-23R-Calmodulin. Type: COMPLEX / Entity ID: #1-#4 / Source: RECOMBINANT | ||||||||||||||||||||
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Molecular weight | Value: 0.168 MDa / Experimental value: YES | ||||||||||||||||||||
Source (natural) | Organism: ![]() ![]() | ||||||||||||||||||||
Source (recombinant) | Organism: ![]() | ||||||||||||||||||||
Buffer solution | pH: 7.4 Details: HEPES-buffered saline (HBS) with added calcium chloride: 25 mM HEPES, pH 7.4, 150 mM NaCl, 5 mM CaCl | ||||||||||||||||||||
Buffer component |
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Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES | ||||||||||||||||||||
Specimen support | Grid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R2/1 | ||||||||||||||||||||
Vitrification | Instrument: LEICA PLUNGER / Cryogen name: ETHANE / Humidity: 95 % / Details: Leica EM GP2, 4.5 s. blotting time. |
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Electron microscopy imaging
Microscopy | Model: JEOL CRYO ARM 300 |
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Electron gun | Electron source: ![]() |
Electron lens | Mode: BRIGHT FIELD / Nominal magnification: 60000 X / Nominal defocus max: 2500 nm / Nominal defocus min: 1000 nm |
Specimen holder | Cryogen: NITROGEN |
Image recording | Average exposure time: 3.37 sec. / Electron dose: 61.8 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of real images: 6660 |
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Processing
EM software | Name: PHENIX / Version: 1.20.1_4487: / Category: model refinement |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION |
Particle selection | Num. of particles selected: 2053974 |
Symmetry | Point symmetry: C1 (asymmetric) |
3D reconstruction | Resolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 315005 / Symmetry type: POINT |
Atomic model building | Protocol: RIGID BODY FIT |