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- PDB-8oe4: Cryo-EM structure of a pre-dimerized human IL-23 complete extrace... -

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Basic information

Entry
Database: PDB / ID: 8oe4
TitleCryo-EM structure of a pre-dimerized human IL-23 complete extracellular signaling complex.
Components
  • (Interleukin-12 ...) x 2
  • (Interleukin-23 ...) x 2
KeywordsSIGNALING PROTEIN / Complex / Cytokine / Receptor
Function / homology
Function and homology information


prolactin receptor activity / late endosome lumen / interleukin-23 receptor binding / interleukin-12 alpha subunit binding / interleukin-12 complex / interleukin-23 complex / natural killer cell activation involved in immune response / negative regulation of vascular endothelial growth factor signaling pathway / positive regulation of natural killer cell activation / positive regulation of natural killer cell mediated cytotoxicity directed against tumor cell target ...prolactin receptor activity / late endosome lumen / interleukin-23 receptor binding / interleukin-12 alpha subunit binding / interleukin-12 complex / interleukin-23 complex / natural killer cell activation involved in immune response / negative regulation of vascular endothelial growth factor signaling pathway / positive regulation of natural killer cell activation / positive regulation of natural killer cell mediated cytotoxicity directed against tumor cell target / negative regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis / positive regulation of lymphocyte proliferation / positive regulation of tissue remodeling / cellular response to hydroperoxide / tissue remodeling / positive regulation of smooth muscle cell apoptotic process / 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 T-helper 1 type immune response / sexual reproduction / positive regulation of mononuclear cell proliferation / interleukin-12 receptor binding / interleukin-12 receptor complex / interleukin-23 receptor complex / T-helper cell differentiation / positive regulation of memory T cell differentiation / interleukin-23-mediated signaling pathway / Interleukin-23 signaling / Caspase activation via Dependence Receptors in the absence of ligand / positive regulation of T-helper 17 type immune response / interleukin-12-mediated signaling pathway / defense response to tumor cell / positive regulation of NK T cell proliferation / negative regulation of interleukin-17 production / positive regulation of osteoclast differentiation / regulation of NMDA receptor activity / Interleukin-12 signaling / calcium/calmodulin-dependent protein kinase activity / cytokine receptor activity / cell surface receptor signaling pathway via STAT / positive regulation of neutrophil chemotaxis / natural killer cell activation / positive regulation of granulocyte macrophage colony-stimulating factor production / response to UV-B / CaM pathway / Cam-PDE 1 activation / Sodium/Calcium exchangers / Calmodulin induced events / syntaxin-1 binding / Reduction of cytosolic Ca++ levels / Activation of Ca-permeable Kainate Receptor / T-helper 1 type immune response / CREB1 phosphorylation through the activation of CaMKII/CaMKK/CaMKIV cascasde / Loss of phosphorylation of MECP2 at T308 / CREB1 phosphorylation through the activation of Adenylate Cyclase / CaMK IV-mediated phosphorylation of CREB / PKA activation / negative regulation of high voltage-gated calcium channel activity / Glycogen breakdown (glycogenolysis) / CLEC7A (Dectin-1) induces NFAT activation / Activation of RAC1 downstream of NMDARs / negative regulation of interleukin-10 production / negative regulation of ryanodine-sensitive calcium-release channel activity / organelle localization by membrane tethering / mitochondrion-endoplasmic reticulum membrane tethering / autophagosome membrane docking / defense response to protozoan / negative regulation of calcium ion export across plasma membrane / regulation of cardiac muscle cell action potential / presynaptic endocytosis / cytokine binding / Synthesis of IP3 and IP4 in the cytosol / regulation of cell communication by electrical coupling involved in cardiac conduction / Phase 0 - rapid depolarisation / Negative regulation of NMDA receptor-mediated neuronal transmission / calcineurin-mediated signaling / Interleukin-10 signaling / Unblocking of NMDA receptors, glutamate binding and activation / positive regulation of activated T cell proliferation / positive regulation of natural killer cell proliferation / positive regulation of interleukin-17 production / RHO GTPases activate PAKs / peptide hormone binding / Ion transport by P-type ATPases / Uptake and function of anthrax toxins / positive regulation of interleukin-10 production / regulation of ryanodine-sensitive calcium-release channel activity / Long-term potentiation / protein phosphatase activator activity / Calcineurin activates NFAT / Regulation of MECP2 expression and activity / extrinsic apoptotic signaling pathway via death domain receptors / DARPP-32 events / catalytic complex / Smooth Muscle Contraction / negative regulation of protein secretion / detection of calcium ion / response to type II interferon
Similarity search - Function
Interleukin-23 alpha / Interleukin 23 subunit alpha / : / Interleukin-12 beta / Interleukin-12 beta, central domain / : / Cytokine interleukin-12p40 C-terminus / Death-associated protein kinase 1 / Long hematopoietin receptor, soluble alpha chain, conserved site / Long hematopoietin receptor, soluble alpha chains family signature. ...Interleukin-23 alpha / Interleukin 23 subunit alpha / : / Interleukin-12 beta / Interleukin-12 beta, central domain / : / Cytokine interleukin-12p40 C-terminus / Death-associated protein kinase 1 / Long hematopoietin receptor, soluble alpha chain, conserved site / Long hematopoietin receptor, soluble alpha chains family signature. / Long hematopoietin receptor, Gp130 family 2, conserved site / Long hematopoietin receptor, gp130 family signature. / Roc domain profile. / Roc domain / Ankyrin repeats (many copies) / Death domain profile. / DEATH domain, found in proteins involved in cell death (apoptosis). / Death domain / Death domain / Four-helical cytokine-like, core / : / Death-like domain superfamily / Ankyrin repeat / Fibronectin type III domain / Fibronectin type 3 domain / Immunoglobulin subtype 2 / Immunoglobulin C-2 Type / EF-hand domain pair / Fibronectin type-III domain profile. / Ankyrin repeats (3 copies) / Fibronectin type III / Fibronectin type III superfamily / Ankyrin repeat profile. / Ankyrin repeat region circular profile. / ankyrin repeats / Ankyrin repeat / EF-hand, calcium binding motif / Ankyrin repeat-containing domain superfamily / EF-Hand 1, calcium-binding site / EF-hand calcium-binding domain. / EF-hand calcium-binding domain profile. / EF-hand domain / EF-hand domain pair / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Immunoglobulin-like fold / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Calmodulin-1 / Interleukin-12 subunit beta / Interleukin-12 receptor subunit beta-1 / Death-associated protein kinase 1 / Interleukin-23 receptor / Interleukin-23 subunit alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.6 Å
AuthorsBloch, Y. / Felix, J. / Savvides, S.N.
Funding support Belgium, 2items
OrganizationGrant numberCountry
Research Foundation - Flanders (FWO)12S0519N Belgium
Research Foundation - Flanders (FWO)G0B4918N Belgium
CitationJournal: Nat Struct Mol Biol / Year: 2024
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
DepositionMar 10, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 7, 2024Provider: repository / Type: Initial release
Revision 1.1May 1, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Nov 20, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Interleukin-12 subunit beta
B: Interleukin-23 subunit alpha
C: Interleukin-23 receptor,Calmodulin-1
D: Interleukin-12 receptor subunit beta-1,Death-associated protein kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)172,1858
Polymers170,5704
Non-polymers1,6154
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration, light scattering, MALLS, electron microscopy
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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Interleukin-12 ... , 2 types, 2 molecules AD

#1: Protein Interleukin-12 subunit beta / IL-12B / Cytotoxic lymphocyte maturation factor 40 kDa subunit / CLMF p40 / IL-12 subunit p40 / NK ...IL-12B / Cytotoxic lymphocyte maturation factor 40 kDa subunit / CLMF p40 / IL-12 subunit p40 / NK cell stimulatory factor chain 2 / NKSF2


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.) Homo sapiens (human) / Gene: IL12B, NKSF2 / Cell line (production host): HEK293 MGAT-/- / Production host: Homo sapiens (human) / References: UniProt: P29460
#4: Protein Interleukin-12 receptor subunit beta-1,Death-associated protein kinase 1 / IL-12 receptor subunit beta-1 / IL-12R subunit beta-1 / IL-12R-beta-1 / IL-12RB1 / IL-12 receptor ...IL-12 receptor subunit beta-1 / IL-12R subunit beta-1 / IL-12R-beta-1 / IL-12RB1 / IL-12 receptor beta component / DAP kinase 1


Mass: 60187.316 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IL12RB1, IL12R, IL12RB, DAPK1, DAPK / Cell line (production host): HEK293 MGAT-/- / Production host: Homo sapiens (human)
References: UniProt: P42701, UniProt: P53355, non-specific serine/threonine protein kinase

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Interleukin-23 ... , 2 types, 2 molecules BC

#2: Protein Interleukin-23 subunit alpha / IL-23 subunit alpha / IL-23-A / Interleukin-23 subunit p19 / IL-23p19


Mass: 20650.117 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IL23A, SGRF, UNQ2498/PRO5798 / Cell line (production host): HEK293 MGAT-/- / Production host: Homo sapiens (human) / References: UniProt: Q9NPF7
#3: Protein Interleukin-23 receptor,Calmodulin-1 / IL-23 receptor / IL-23R


Mass: 54991.391 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IL23R, CALM1, CALM, CAM, CAM1 / Cell line (production host): HEK293 MGAT-/- / Production host: Homo sapiens (human) / References: UniProt: Q5VWK5, UniProt: P0DP23

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Sugars , 3 types, 4 molecules

#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


Type: oligosaccharide / Mass: 748.682 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-3DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/3,4,3/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3/a4-b1_b4-c1_c3-d1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{}}}}LINUCSPDB-CARE
#6: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#7: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Details

Has ligand of interestN
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Human IL-23 in complex with hIL-12Rbeta1-DAPK1 and hIL-23R-Calmodulin.
Type: COMPLEX / Entity ID: #1-#4 / Source: RECOMBINANT
Molecular weightValue: 0.168 MDa / Experimental value: YES
Source (natural)Organism: Mus musculus (house mouse)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 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
IDConc.NameFormulaBuffer-ID
1150 mMsodium chlorideNaCl1
225 mMHEPESC8H18N2O4S1
35 mMcalcium chlorideCaCl1
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R2/1
VitrificationInstrument: LEICA PLUNGER / Cryogen name: ETHANE / Humidity: 95 % / Details: Leica EM GP2, 4.5 s. blotting time.

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Electron microscopy imaging

MicroscopyModel: JEOL CRYO ARM 300
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 60000 X / Nominal defocus max: 2500 nm / Nominal defocus min: 1000 nm
Specimen holderCryogen: NITROGEN
Image recordingAverage 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 softwareName: PHENIX / Version: 1.20.1_4487: / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 2053974
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 315005 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT

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