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- EMDB-16824: Cryo-EM structure of a pre-dimerized human IL-23 complete extrace... -
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Open data
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Basic information
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Title | Cryo-EM structure of a pre-dimerized human IL-23 complete extracellular signaling complex. | |||||||||
![]() | Main map: Unfiltered, non-sharpened map of the human IL23:IL12Rbeta1-DAPK1:IL23R-Calmodulin complex used for model refinement in Phenix. Additional map: deepEMhancer sharpened map. | |||||||||
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![]() | Complex / Cytokine / Receptor / SIGNALING PROTEIN | |||||||||
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 neutrophil chemotaxis / Interleukin-12 signaling / response to UV-B / regulation of NMDA receptor activity / CaM pathway / Cam-PDE 1 activation / cytokine receptor activity / positive regulation of natural killer cell proliferation / 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 / extrinsic apoptotic signaling pathway via death domain receptors Similarity search - Function | |||||||||
Biological species | ![]() ![]() ![]() | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.6 Å | |||||||||
![]() | Bloch Y / Felix J / Savvides SN | |||||||||
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
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 116.1 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 24.7 KB 24.7 KB | Display Display | ![]() |
FSC (resolution estimation) | ![]() | 10.6 KB | Display | ![]() |
Images | ![]() | 72.8 KB | ||
Masks | ![]() | 125 MB | ![]() | |
Filedesc metadata | ![]() | 7.7 KB | ||
Others | ![]() ![]() ![]() | 107.7 MB 116.1 MB 116.1 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 8oe4MC ![]() 8c7mC ![]() 8cr5C ![]() 8cr6C ![]() 8cr8C ![]() 8odxC ![]() 8odzC ![]() 8oe0C ![]() 8pb1C ![]() 8ppmC C: citing same article ( M: atomic model generated by this map |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Annotation | Main map: Unfiltered, non-sharpened map of the human IL23:IL12Rbeta1-DAPK1:IL23R-Calmodulin complex used for model refinement in Phenix. Additional map: deepEMhancer sharpened map. | ||||||||||||||||||||
Voxel size | X=Y=Z: 0.9815 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Mask #1
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Projections & Slices |
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Density Histograms |
-Additional map: DeepEMhancer sharpened map of the human IL23:IL12Rbeta1-DAPK1:IL23R-Calmodulin complex,...
File | emd_16824_additional_1.map | ||||||||||||
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Annotation | DeepEMhancer sharpened map of the human IL23:IL12Rbeta1-DAPK1:IL23R-Calmodulin complex, used for model building in Coot and visualization. | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: Half map 2 of the human IL23:IL12Rbeta1-DAPK1:IL23R-Calmodulin complex....
File | emd_16824_half_map_1.map | ||||||||||||
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Annotation | Half map 2 of the human IL23:IL12Rbeta1-DAPK1:IL23R-Calmodulin complex. | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: Half map 1 of the human IL23:IL12Rbeta1-DAPK1:IL23R-Calmodulin complex....
File | emd_16824_half_map_2.map | ||||||||||||
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Annotation | Half map 1 of the human IL23:IL12Rbeta1-DAPK1:IL23R-Calmodulin complex. | ||||||||||||
Projections & Slices |
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Density Histograms |
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Sample components
-Entire : Human IL-23 in complex with hIL-12Rbeta1-DAPK1 and hIL-23R-Calmodulin.
Entire | Name: Human IL-23 in complex with hIL-12Rbeta1-DAPK1 and hIL-23R-Calmodulin. |
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Components |
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-Supramolecule #1: Human IL-23 in complex with hIL-12Rbeta1-DAPK1 and hIL-23R-Calmodulin.
Supramolecule | Name: Human IL-23 in complex with hIL-12Rbeta1-DAPK1 and hIL-23R-Calmodulin. type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4 |
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Source (natural) | Organism: ![]() ![]() |
Molecular weight | Theoretical: 168 KDa |
-Macromolecule #1: Interleukin-12 subunit beta
Macromolecule | Name: Interleukin-12 subunit beta / type: protein_or_peptide / ID: 1 Details: N-glycosylation mutant: Asparagine 303 (N303) is mutated to Aspartic acid (D303). Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 34.74093 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: IWELKKDVYV VELDWYPDAP GEMVVLTCDT PEEDGITWTL DQSSEVLGSG KTLTIQVKEF GDAGQYTCHK GGEVLSHSLL LLHKKEDGI WSTDILKDQK EPKNKTFLRC EAKNYSGRFT CWWLTTISTD LTFSVKSSRG SSDPQGVTCG AATLSAERVR G DNKEYEYS ...String: IWELKKDVYV VELDWYPDAP GEMVVLTCDT PEEDGITWTL DQSSEVLGSG KTLTIQVKEF GDAGQYTCHK GGEVLSHSLL LLHKKEDGI WSTDILKDQK EPKNKTFLRC EAKNYSGRFT CWWLTTISTD LTFSVKSSRG SSDPQGVTCG AATLSAERVR G DNKEYEYS VECQEDSACP AAEESLPIEV MVDAVHKLKY ENYTSSFFIR DIIKPDPPKN LQLKPLKNSR QVEVSWEYPD TW STPHSYF SLTFCVQVQG KSKREKKDRV FTDKTSATVI CRKDASISVR AQDRYYSSSW SEWASVPCS UniProtKB: Interleukin-12 subunit beta |
-Macromolecule #2: Interleukin-23 subunit alpha
Macromolecule | Name: Interleukin-23 subunit alpha / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 20.650117 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: RAVPGGSSPA WTQCQQLSQK LCTLAWSAHP LVGHMDLREE GDEETTNDVP HIQCGDGCDP QGLRDNSQFC LQRIHQGLIF YEKLLGSDI FTGEPSLLPD SPVGQLHASL LGLSQLLQPE GHHWETQQIP SLSPSQPWQR LLLRFKILRS LQAFVAVAAR V FAHGAATL SPGDEVDGHH HHHHHHHH UniProtKB: Interleukin-23 subunit alpha |
-Macromolecule #3: Interleukin-23 receptor,Calmodulin-1
Macromolecule | Name: Interleukin-23 receptor,Calmodulin-1 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 54.991391 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: GITNINCSGH IWVEPATIFK MGMNISIYCQ AAIKNCQPRK LHFYKNGIKE RFQITRINKT TARLWYKNFL EPHASMYCTA ECPKHFQET LICGKDISSG YPPDIPDEVT CVIYEYSGNM TCTWNAGKLT YIDTKYVVHV KSLETEEEQQ YLTSSYINIS T DSLQGGKK ...String: GITNINCSGH IWVEPATIFK MGMNISIYCQ AAIKNCQPRK LHFYKNGIKE RFQITRINKT TARLWYKNFL EPHASMYCTA ECPKHFQET LICGKDISSG YPPDIPDEVT CVIYEYSGNM TCTWNAGKLT YIDTKYVVHV KSLETEEEQQ YLTSSYINIS T DSLQGGKK YLVWVQAANA LGMEESKQLQ IHLDDIVIPS AAVISRAETI NATVPKTIIY WDSQTTIEKV SCEMRYKATT NQ TWNVKEF DTNFTYVQQS EFYLEPNIKY VFQVRCQETG KRYWQPWSSL FFHKTPETVP QVTSKAFQHD TWNSGLTVAS IST GHLTSD NRGDGTGGSG GSGGLTEEQI AEFKEAFSLF DKDGDGTITT KELGTVMRSL GQNPTEAELQ DMINEVDADG NGTI DFPEF LTMMARKMKD TDSEEEIREA FRVFDKDGNG YISAAELRHV MTNLGEKLTD EEVDEMIREA DIDGDGQVNY EEFVQ MMTA K UniProtKB: Interleukin-23 receptor, Calmodulin-1 |
-Macromolecule #4: Interleukin-12 receptor subunit beta-1,Death-associated protein k...
Macromolecule | Name: Interleukin-12 receptor subunit beta-1,Death-associated protein kinase 1 type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO / EC number: non-specific serine/threonine protein kinase |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 60.187316 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: CRTSECCFQD PPYPDADSGS ASGPRDLRCY RISSDRYECS WQYEGPTAGV SHFLRCCLSS GRCCYFAAGS ATRLQFSDQA GVSVLYTVT LWVESWARNQ TEKSPEVTLQ LYNSVKYEPP LGDIKVSKLA GQLRMEWETP DNQVGAEVQF RHRTPSSPWK L GDCGPQDD ...String: CRTSECCFQD PPYPDADSGS ASGPRDLRCY RISSDRYECS WQYEGPTAGV SHFLRCCLSS GRCCYFAAGS ATRLQFSDQA GVSVLYTVT LWVESWARNQ TEKSPEVTLQ LYNSVKYEPP LGDIKVSKLA GQLRMEWETP DNQVGAEVQF RHRTPSSPWK L GDCGPQDD DTESCLCPLE MNVAQEFQLR RRQLGSQGSS WSKWSSPVCV PPENPPQPQV RFSVEQLGQD GRRRLTLKEQ PT QLELPEG CQGLAPGTEV TYRLQLHMLS CPCKAKATRT LHLGKMPYLS GAAYNVAVIS SNQFGPGLNQ TWHIPADTHT EPV ALNISV GTNGTTMYWP ARAQSMTYCI EWQPVGQDGG LATCSLTAPQ DPDPAGMATY SWSRESGAMG QEKCYYITIF ASAH PEKLT LWSTVLSTYH FGGNASAAGT PHHVSVKNHS LDSVSVDWAP SLLSTCPGVL KEYVVRCRDE DSKQVSEHPV QPTET QVTL SGLRAGVAYT VQVRADTAWL RGVWSQPQRF SIEGTGGSGG SGGAARKKWK QSVRLISLCQ RLS UniProtKB: Interleukin-12 receptor subunit beta-1, Death-associated protein kinase 1 |
-Macromolecule #7: 2-acetamido-2-deoxy-beta-D-glucopyranose
Macromolecule | Name: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 7 / Number of copies: 2 / Formula: NAG |
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Molecular weight | Theoretical: 221.208 Da |
Chemical component information | ![]() ChemComp-NAG: |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Buffer | pH: 7.4 Component:
Details: HEPES-buffered saline (HBS) with added calcium chloride: 25 mM HEPES, pH 7.4, 150 mM NaCl, 5 mM CaCl | ||||||||||||
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Grid | Model: Quantifoil R2/1 / Material: COPPER / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE | ||||||||||||
Vitrification | Cryogen name: ETHANE / Chamber humidity: 95 % / Instrument: LEICA PLUNGER / Details: Leica EM GP2, 4.5 s. blotting time.. |
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Electron microscopy
Microscope | JEOL CRYO ARM 300 |
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Image recording | Film or detector model: GATAN K3 (6k x 4k) / Number real images: 6660 / Average exposure time: 3.37 sec. / Average electron dose: 61.8 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.0 µm / Nominal magnification: 60000 |
Sample stage | Cooling holder cryogen: NITROGEN |
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Image processing
-Atomic model buiding 1
Refinement | Protocol: RIGID BODY FIT |
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Output model | ![]() PDB-8oe4: |