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- PDB-8yi7: The Cryo-EM structure of IL-12, receptor subunit beta-1 and recep... -

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Basic information

Entry
Database: PDB / ID: 8yi7
TitleThe Cryo-EM structure of IL-12, receptor subunit beta-1 and receptor subunit beta-2 complex, local refinement
Components
  • (Interleukin-12 receptor subunit beta- ...) x 2
  • (Interleukin-12 subunit ...) x 2
KeywordsCYTOKINE / IL-12 / IL-12RB1 / IL-12RB2 / receptor complex
Function / homology
Function and homology information


interleukin-27 binding / interleukin-12 beta subunit binding / late endosome lumen / interleukin-12 alpha subunit binding / interleukin-12 complex / interleukin-23 complex / natural killer cell activation involved in immune response / positive regulation of dendritic cell chemotaxis / positive regulation of natural killer cell activation / positive regulation of natural killer cell mediated cytotoxicity directed against tumor cell target ...interleukin-27 binding / interleukin-12 beta subunit binding / late endosome lumen / interleukin-12 alpha subunit binding / interleukin-12 complex / interleukin-23 complex / natural killer cell activation involved in immune response / positive regulation of dendritic cell chemotaxis / positive regulation of natural killer cell activation / 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 lymphocyte proliferation / positive regulation of tissue remodeling / positive regulation of T-helper 1 type immune response / sexual reproduction / positive regulation of NK T cell activation / positive regulation of smooth muscle cell apoptotic process / positive regulation of natural killer cell mediated cytotoxicity / positive regulation of mononuclear cell proliferation / interleukin-23-mediated signaling pathway / interleukin-12 receptor binding / interleukin-12 receptor complex / positive regulation of memory T cell differentiation / T-helper cell differentiation / interleukin-23 receptor complex / natural killer cell activation / Interleukin-23 signaling / positive regulation of T-helper 17 type immune response / positive regulation of osteoclast differentiation / interleukin-12-mediated signaling pathway / negative regulation of interleukin-17 production / positive regulation of NK T cell proliferation / Interleukin-12 signaling / Interleukin-35 Signalling / response to UV-B / positive regulation of natural killer cell proliferation / positive regulation of granulocyte macrophage colony-stimulating factor production / cytokine receptor activity / T-helper 1 type immune response / negative regulation of interleukin-10 production / defense response to protozoan / positive regulation of activated T cell proliferation / cytokine binding / positive regulation of interleukin-17 production / Interleukin-10 signaling / cell surface receptor signaling pathway via JAK-STAT / positive regulation of interleukin-10 production / negative regulation of protein secretion / positive regulation of defense response to virus by host / coreceptor activity / positive regulation of T-helper 17 cell lineage commitment / positive regulation of T cell proliferation / T cell proliferation / positive regulation of tyrosine phosphorylation of STAT protein / extrinsic apoptotic signaling pathway / regulation of cytokine production / positive regulation of interleukin-12 production / positive regulation of cell adhesion / cytokine activity / negative regulation of inflammatory response to antigenic stimulus / negative regulation of smooth muscle cell proliferation / growth factor activity / response to virus / cellular response to virus / cellular response to type II interferon / cytokine-mediated signaling pathway / positive regulation of inflammatory response / positive regulation of T cell mediated cytotoxicity / positive regulation of non-canonical NF-kappaB signal transduction / positive regulation of type II interferon production / positive regulation of tumor necrosis factor production / cell migration / cellular response to lipopolysaccharide / Interleukin-4 and Interleukin-13 signaling / defense response to virus / defense response to Gram-negative bacterium / response to lipopolysaccharide / receptor complex / cell surface receptor signaling pathway / defense response to Gram-positive bacterium / immune response / protein heterodimerization activity / endoplasmic reticulum lumen / external side of plasma membrane / positive regulation of cell population proliferation / protein-containing complex binding / protein kinase binding / signal transduction / extracellular space / extracellular region / identical protein binding / plasma membrane / cytosol
Similarity search - Function
Interleukin-12 alpha / Interleukin-12 alpha subunit / Interleukin-12 beta / Interleukin-12 beta, central domain / : / Cytokine interleukin-12p40 C-terminus / Long hematopoietin receptor, soluble alpha chain, conserved site / Long hematopoietin receptor, soluble alpha chains family signature. / Immunoglobulin C2-set-like, ligand-binding / Ig-like C2-type domain ...Interleukin-12 alpha / Interleukin-12 alpha subunit / Interleukin-12 beta / Interleukin-12 beta, central domain / : / Cytokine interleukin-12p40 C-terminus / Long hematopoietin receptor, soluble alpha chain, conserved site / Long hematopoietin receptor, soluble alpha chains family signature. / Immunoglobulin C2-set-like, ligand-binding / Ig-like C2-type domain / Long hematopoietin receptor, Gp130 family 2, conserved site / Long hematopoietin receptor, gp130 family signature. / : / Four-helical cytokine-like, core / Fibronectin type III domain / Fibronectin type 3 domain / Immunoglobulin subtype 2 / Immunoglobulin C-2 Type / Fibronectin type-III domain profile. / Fibronectin type III / Fibronectin type III superfamily / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Immunoglobulin-like fold
Similarity search - Domain/homology
Interleukin-12 subunit alpha / Interleukin-12 subunit beta / Interleukin-12 receptor subunit beta-1 / Interleukin-12 receptor subunit beta-2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.57 Å
AuthorsChen, H.Q. / Ge, X.F.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Structure / Year: 2024
Title: Structure and assembly of the human IL-12 signaling complex.
Authors: Huiqin Chen / Xiaofei Ge / Chun Li / Jianwei Zeng / Xinquan Wang /
Abstract: Interleukin (IL)-12 is a heterodimeric pro-inflammatory cytokine. Our cryoelectron microscopy structure determination of human IL-12 in complex with IL-12Rβ1 and IL-12Rβ2 at a resolution of 3. ...Interleukin (IL)-12 is a heterodimeric pro-inflammatory cytokine. Our cryoelectron microscopy structure determination of human IL-12 in complex with IL-12Rβ1 and IL-12Rβ2 at a resolution of 3.75 Å reveals that IL-12Rβ2 primarily interacts with the IL-12p35 subunit via its N-terminal Ig-like domain, while IL-12Rβ1 binds to the p40 subunit with its N-terminal fibronectin III domain. This binding mode of IL-12 with its receptors is similar to that of IL-23 but shows notable differences with other cytokines. Through structural information and biochemical assays, we identified Y62, Y189, and K192 as key residues in IL-12p35, which bind to IL-12Rβ2 with high affinity and mediate IL-12 signal transduction. Furthermore, structural comparisons reveal two distinctive conformational states and structural plasticity of the heterodimeric interface in IL-12. As a result, our study advances our understanding of IL-12 signal initiation and opens up new opportunities for the engineering and therapeutic targeting of IL-12.
History
DepositionFeb 29, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jul 24, 2024Provider: repository / Type: Initial release
Revision 1.1Aug 14, 2024Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.title / _citation.year / _em_admin.last_update
Revision 1.2Aug 21, 2024Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.pdbx_database_id_PubMed / _citation_author.identifier_ORCID ..._citation.pdbx_database_id_PubMed / _citation_author.identifier_ORCID / _citation_author.name / _em_admin.last_update
Revision 1.3Oct 30, 2024Group: Data collection / Database references / Structure summary
Category: citation / em_admin ...citation / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _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 alpha
B: Interleukin-12 subunit beta
C: Interleukin-12 receptor subunit beta-2
D: Interleukin-12 receptor subunit beta-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)118,7646
Polymers117,9564
Non-polymers8082
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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Interleukin-12 subunit ... , 2 types, 2 molecules AB

#1: Protein Interleukin-12 subunit alpha / IL-12A / Cytotoxic lymphocyte maturation factor 35 kDa subunit / CLMF p35 / IL-12 subunit p35 / NK ...IL-12A / Cytotoxic lymphocyte maturation factor 35 kDa subunit / CLMF p35 / IL-12 subunit p35 / NK cell stimulatory factor chain 1 / NKSF1


Mass: 23781.508 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IL12A, NKSF1 / Production host: Baculovirus expression vector pFastBac1-HM / References: UniProt: P29459
#2: 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: 34811.023 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IL12B, NKSF2 / Production host: Baculovirus expression vector pFastBac1-HM / References: UniProt: P29460

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Interleukin-12 receptor subunit beta- ... , 2 types, 2 molecules CD

#3: Protein Interleukin-12 receptor subunit beta-2 / IL-12 receptor subunit beta-2 / IL-12R subunit beta-2 / IL-12R-beta-2 / IL-12RB2


Mass: 34627.477 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IL12RB2 / Production host: Baculovirus expression vector pFastBac1-HM / References: UniProt: Q99665
#4: Protein Interleukin-12 receptor subunit beta-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


Mass: 24736.449 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IL12RB1, IL12R, IL12RB / Production host: Baculovirus expression vector pFastBac1-HM / References: UniProt: P42701

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Sugars , 2 types, 2 molecules

#5: Polysaccharide beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta- ...beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 586.542 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/2,3,2/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5]/1-1-2/a4-b1_b4-c1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{}}}LINUCSPDB-CARE
#6: 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.: 1 / Source method: obtained synthetically / Formula: C8H15NO6 / Feature type: SUBJECT OF INVESTIGATION
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 interestY
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: the ternary complex of IL-12 with IL-12R beta-1 and IL-12R beta-2
Type: COMPLEX / Entity ID: #1-#4 / Source: RECOMBINANT
Molecular weightValue: 0.120 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Baculovirus expression vector pFastBac1-HM
Buffer solutionpH: 8
Buffer component
IDConc.NameFormulaBuffer-ID
1150 mMsodium chlorideNaCl1
225 mMTris-HClTris-HCl1
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 500 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.57 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 332015 / Symmetry type: POINT

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