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- EMDB-38609: The Cryo-EM structure of IL-12, receptor subunit beta-1 and recep... -

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Entry
Database: EMDB / ID: EMD-38609
TitleThe Cryo-EM structure of IL-12, receptor subunit beta-1 and receptor subunit beta-2 complex
Map dataIt is a density map generated in C1 symmetry. The central region has a resolution close to 3 angstrom, while the peripheral region exhibited weaker density with low resolution.
Sample
  • Complex: The Cryo-EM structure of IL-12, receptor subunit beta-1 and receptor subunit beta-2 complex
    • Protein or peptide: Interleukin-12 subunit alpha
    • Protein or peptide: Interleukin-12 subunit beta
    • Protein or peptide: Interleukin-12 receptor subunit beta-2
    • Protein or peptide: Interleukin-12 receptor subunit beta-1
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
KeywordsIL-12 / IL-12RB1 / IL-12RB2 / receptor complex / CYTOKINE
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)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.75 Å
AuthorsChen HQ / Wang XQ / Ge XF / Zeng JW / Wang JW
Funding support China, 1 items
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
DepositionJan 7, 2024-
Header (metadata) releaseJul 24, 2024-
Map releaseJul 24, 2024-
UpdateNov 6, 2024-
Current statusNov 6, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_38609.png

Downloads & links

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Map

FileDownload / File: emd_38609.map.gz / Format: CCP4 / Size: 421.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationIt is a density map generated in C1 symmetry. The central region has a resolution close to 3 angstrom, while the peripheral region exhibited weaker density with low resolution.
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.87 Å/pix.
x 480 pix.
= 417.456 Å		0.87 Å/pix.
x 480 pix.
= 417.456 Å		0.87 Å/pix.
x 480 pix.
= 417.456 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.8697 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.125
Minimum - Maximum-0.8917472 - 1.6351179
Average (Standard dev.)-0.00040954445 (±0.030161653)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions480480480
Spacing480480480
CellA=B=C: 417.456 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: map half A

Fileemd_38609_half_map_1.map
Annotationmap_half_A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: map half B

Fileemd_38609_half_map_2.map
Annotationmap_half_B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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

EntireName: The Cryo-EM structure of IL-12, receptor subunit beta-1 and receptor subunit beta-2 complex
Components
  • Complex: The Cryo-EM structure of IL-12, receptor subunit beta-1 and receptor subunit beta-2 complex
    • Protein or peptide: Interleukin-12 subunit alpha
    • Protein or peptide: Interleukin-12 subunit beta
    • Protein or peptide: Interleukin-12 receptor subunit beta-2
    • Protein or peptide: Interleukin-12 receptor subunit beta-1
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: The Cryo-EM structure of IL-12, receptor subunit beta-1 and recep...

SupramoleculeName: The Cryo-EM structure of IL-12, receptor subunit beta-1 and receptor subunit beta-2 complex
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 485 KDa

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Macromolecule #1: Interleukin-12 subunit alpha

MacromoleculeName: Interleukin-12 subunit alpha / type: protein_or_peptide / ID: 1 / Details: Interleukin-12 subunit alpha / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.781508 KDa
Recombinant expressionOrganism: Baculovirus expression vector pFastBac1-HM
SequenceString: LSLARNLPVA TPDPGMFPCL HHSQNLLRAV SNMLQKARQT LEFYPCTSEE IDHEDITKDK TSTVEACLPL ELTKNESCLN SRETSFITN GSCLASRKTS FMMALCLSSI YEDLKMYQVE FKTMNAKLLM DPKRQIFLDQ NMLAVIDELM QALNFNSETV P QKSSLEEP ...String:
LSLARNLPVA TPDPGMFPCL HHSQNLLRAV SNMLQKARQT LEFYPCTSEE IDHEDITKDK TSTVEACLPL ELTKNESCLN SRETSFITN GSCLASRKTS FMMALCLSSI YEDLKMYQVE FKTMNAKLLM DPKRQIFLDQ NMLAVIDELM QALNFNSETV P QKSSLEEP DFYKTKIKLC ILLHAFRIRA VTIDRVMSYL NASHHHHHH

UniProtKB: Interleukin-12 subunit alpha

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Macromolecule #2: Interleukin-12 subunit beta

MacromoleculeName: Interleukin-12 subunit beta / type: protein_or_peptide / ID: 2 / Details: Interleukin-12 subunit beta / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 34.811023 KDa
Recombinant expressionOrganism: Baculovirus expression vector pFastBac1-HM
SequenceString: AIWELKKDVY VVELDWYPDA PGEMVVLTCD TPEEDGITWT LDQSSEVLGS GKTLTIQVKE FGDAGQYTCH KGGEVLSHSL LLLHKKEDG IWSTDILKDQ KEPKNKTFLR CEAKNYSGRF TCWWLTTIST DLTFSVKSSR GSSDPQGVTC GAATLSAERV R GDNKEYEY ...String:
AIWELKKDVY VVELDWYPDA PGEMVVLTCD TPEEDGITWT LDQSSEVLGS GKTLTIQVKE FGDAGQYTCH KGGEVLSHSL LLLHKKEDG IWSTDILKDQ KEPKNKTFLR CEAKNYSGRF TCWWLTTIST DLTFSVKSSR GSSDPQGVTC GAATLSAERV R GDNKEYEY SVECQEDSAC PAAEESLPIE VMVDAVHKLK YENYTSSFFI RDIIKPDPPK NLQLKPLKNS RQVEVSWEYP DT WSTPHSY FSLTFCVQVQ GKSKREKKDR VFTDKTSATV ICRKNASISV RAQDRYYSSS WSEWASVPCS

UniProtKB: Interleukin-12 subunit beta

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Macromolecule #3: Interleukin-12 receptor subunit beta-2

MacromoleculeName: Interleukin-12 receptor subunit beta-2 / type: protein_or_peptide / ID: 3 / Details: Interleukin-12 receptor subunit beta-2 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 34.627477 KDa
Recombinant expressionOrganism: Baculovirus expression vector pFastBac1-HM
SequenceString: KIDACKRGDV TVKPSHVILL GSTVNITCSL KPRQGCFHYS RRNKLILYKF DRRINFHHGH SLNSQVTGLP LGTTLFVCKL ACINSDEIQ ICGAEIFVGV APEQPQNLSC IQKGEQGTVA CTWERGRDTH LYTEYTLQLS GPKNLTWQKQ CKDIYCDYLD F GINLTPES ...String:
KIDACKRGDV TVKPSHVILL GSTVNITCSL KPRQGCFHYS RRNKLILYKF DRRINFHHGH SLNSQVTGLP LGTTLFVCKL ACINSDEIQ ICGAEIFVGV APEQPQNLSC IQKGEQGTVA CTWERGRDTH LYTEYTLQLS GPKNLTWQKQ CKDIYCDYLD F GINLTPES PESNFTAKVT AVNSLGSSSS LPSTFTFLDI VRPLPPWDIR IKFQKASVSR CTLYWRDEGL VLLNRLRYRP SN SRLWNMV NVTKAKGRHD LLDLKPFTEY EFQISSKLHL YKGSWSDWSE SLRAQTPEEH HHHHH

UniProtKB: Interleukin-12 receptor subunit beta-2

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Macromolecule #4: Interleukin-12 receptor subunit beta-1

MacromoleculeName: Interleukin-12 receptor subunit beta-1 / type: protein_or_peptide / ID: 4 / Details: Interleukin-12 receptor subunit beta-1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 24.736449 KDa
Recombinant expressionOrganism: Baculovirus expression vector pFastBac1-HM
SequenceString: 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 PPENPHHHHH H

UniProtKB: Interleukin-12 receptor subunit beta-1

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Macromolecule #6: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 6 / Number of copies: 12 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration1.34 mg/mL
BufferpH: 8
Component:
ConcentrationFormulaName
25.0 mMTris-HClTris-HCl
150.0 mMNaClNaCl

Details: 25mM Tris-HCl pH 8.0,150mM NaCl
GridModel: Quantifoil / Material: GOLD / Mesh: 300 / Support film - Material: CARBON / Support film - topology: LACEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 120 sec.
VitrificationCryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 4547423
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.75 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 423691
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION

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