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- PDB-8cr5: Murine Interleukin-12 receptor beta 1 domain 1 in complex with mu... -

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Basic information

Entry
Database: PDB / ID: 8cr5
TitleMurine Interleukin-12 receptor beta 1 domain 1 in complex with murine Interleukin-12 beta.
Components
  • Interleukin-12 receptor subunit beta-1
  • Interleukin-12 subunit beta
KeywordsCYTOKINE / complex / inflammation / glycoprotein / immunity
Function / homology
Function and homology information


Interleukin-12 signaling / Interleukin-23 signaling / 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 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 ...Interleukin-12 signaling / Interleukin-23 signaling / 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 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 T-helper 1 type immune response / positive regulation of smooth muscle cell apoptotic process / natural killer cell activation / T-helper cell differentiation / interleukin-23 receptor complex / positive regulation of osteoclast differentiation / negative regulation of interleukin-17 production / positive regulation of NK T cell proliferation / interleukin-12-mediated signaling pathway / response to UV-B / positive regulation of natural killer cell proliferation / positive regulation of granulocyte macrophage colony-stimulating factor production / cytokine receptor activity / negative regulation of interleukin-10 production / positive regulation of activated T cell proliferation / defense response to protozoan / positive regulation of interleukin-17 production / cytokine binding / positive regulation of interleukin-10 production / immunoglobulin mediated immune response / negative regulation of protein secretion / T cell proliferation / positive regulation of T cell proliferation / positive regulation of tyrosine phosphorylation of STAT protein / positive regulation of defense response to virus by host / negative regulation of inflammatory response to antigenic stimulus / positive regulation of interleukin-12 production / : / cytokine activity / endosome lumen / negative regulation of smooth muscle cell proliferation / growth factor activity / cytokine-mediated signaling pathway / cellular response to type II interferon / Golgi lumen / positive regulation of T cell mediated cytotoxicity / positive regulation of tumor necrosis factor production / positive regulation of type II interferon production / cell migration / cellular response to lipopolysaccharide / defense response to Gram-negative bacterium / defense response to virus / cell population proliferation / cell surface receptor signaling pathway / receptor complex / protein heterodimerization activity / endoplasmic reticulum lumen / external side of plasma membrane / protein-containing complex binding / cell surface / extracellular space / extracellular region / identical protein binding / plasma membrane / cytoplasm
Similarity search - Function
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. / Fibronectin type III domain / Fibronectin type 3 domain / Immunoglobulin subtype 2 / Immunoglobulin C-2 Type / Fibronectin type-III domain profile. ...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. / 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 beta / Interleukin-12 receptor subunit beta-1
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.15 Å
AuthorsMerceron, R. / Bloch, 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 7, 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

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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-12 receptor subunit beta-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)69,9644
Polymers68,9942
Non-polymers9702
Water2,036113
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, Part of larger complex imaged by single particle cryo EM as well as crystallography.
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3330 Å2
ΔGint17 kcal/mol
Surface area21900 Å2
MethodPISA
Unit cell
Length a, b, c (Å)29.220, 165.090, 51.870
Angle α, β, γ (deg.)90.000, 90.435, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb

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Components

#1: Protein Interleukin-12 subunit beta / IL-12B / Cytotoxic lymphocyte maturation factor 40 kDa subunit / CLMF p40 / IL-12 subunit p40


Mass: 39382.527 Da / Num. of mol.: 1 / Mutation: C197S
Source method: isolated from a genetically manipulated source
Details: residues [M1-A22] encode the signal peptide which is most likely removed during translation/folding. residues [G336-H343] encode for cloning scar and purification tag.
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Il12b / Plasmid: pHLsec / Cell line (production host): HEK293S MGAT1-/- / Production host: Homo sapiens (human) / References: UniProt: P43432
#2: Protein Interleukin-12 receptor subunit beta-1 / IL-12 receptor subunit beta-1 / IL-12R subunit beta-1 / IL-12R-beta-1 / IL-12 receptor beta component


Mass: 29611.381 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: Residues [M1-C19] encode the signal peptide which is most likely removed during translation/folding. Residues [G259-H266] encode a cloning scar and purification tag. Serendipitous in-drop ...Details: Residues [M1-C19] encode the signal peptide which is most likely removed during translation/folding. Residues [G259-H266] encode a cloning scar and purification tag. Serendipitous in-drop proteolysis removed the C-terminal half of the protein.
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Il12rb1, Il12rb / Plasmid: pHLsec / Cell line (production host): HEK293S MGat1-/- / Production host: Homo sapiens (human) / References: UniProt: Q60837
#3: 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
#4: 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: 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
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 113 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestN

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.67 Å3/Da / Density % sol: 53.89 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: (BCS E4) 20% PEG smear medium, 0.1M MgCl2, 0.1 M KCl, 0.1M PIPES pH 7.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: PETRA III, EMBL c/o DESY / Beamline: P13 (MX1) / Wavelength: 1.008 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Apr 28, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.008 Å / Relative weight: 1
ReflectionResolution: 2.15→165 Å / Num. obs: 26490 / % possible obs: 99.5 % / Redundancy: 3.558 % / Biso Wilson estimate: 38.3 Å2 / CC1/2: 0.992 / Rrim(I) all: 0.172 / Net I/σ(I): 7.18
Reflection shellResolution: 2.15→2.21 Å / Redundancy: 3.687 % / Mean I/σ(I) obs: 1.02 / Num. unique obs: 1969 / CC1/2: 0.641 / Rrim(I) all: 1.312 / % possible all: 99.5

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.15→49.48 Å / SU ML: 0.3377 / Cross valid method: FREE R-VALUE / σ(F): 1.37 / Phase error: 35.7455
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2821 1324 5 %
Rwork0.2412 25144 -
obs0.2432 26468 99.35 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 64.03 Å2
Refinement stepCycle: LAST / Resolution: 2.15→49.48 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3167 0 64 113 3344
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00353334
X-RAY DIFFRACTIONf_angle_d0.65444543
X-RAY DIFFRACTIONf_chiral_restr0.0448513
X-RAY DIFFRACTIONf_plane_restr0.0042574
X-RAY DIFFRACTIONf_dihedral_angle_d15.54221195
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.15-2.240.411480.37792807X-RAY DIFFRACTION99.23
2.24-2.340.34961450.35182753X-RAY DIFFRACTION99.42
2.34-2.460.37051490.31622832X-RAY DIFFRACTION99.6
2.46-2.620.35851460.30512781X-RAY DIFFRACTION99.49
2.62-2.820.34351460.30832767X-RAY DIFFRACTION99.32
2.82-3.10.32221460.28182784X-RAY DIFFRACTION99.15
3.1-3.550.29331470.2442777X-RAY DIFFRACTION98.78
3.55-4.470.21361470.18232806X-RAY DIFFRACTION99.76
4.47-49.480.2421500.19232837X-RAY DIFFRACTION99.43
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
12.039063758641.014025725510.3880084410343.110218622351.106989765541.385274429090.0376099827183-0.1604087778250.3716034460360.05128027470450.0400137618633-0.0705876303281-0.309316265403-0.07067250136140.001116387925890.4049939812880.03429697074620.0306352587410.367872678165-0.0002792649315180.4157972370944.65451803187-35.677348460316.8432342411
23.514807819420.354524242806-0.6246097036422.83954804622-0.01883740353240.9558560304560.0145170069675-0.0369328938005-0.5779880641750.148841499975-0.0644462986694-0.1273785658370.247594467819-0.0786746632007-0.002422838331330.285566370891-0.0223121711728-0.02948342770490.312517572453-0.04870620853290.348911043481-9.03310664191-69.919535281420.2020938003
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION / Label seq-ID: 1

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-ID
11(chain 'A' )AA - E23 - 403
22(chain 'B' )BB - F46 - 180

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