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- PDB-8cr8: human Interleukin-23 -

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Basic information

Entry
Database: PDB / ID: 8cr8
Titlehuman Interleukin-23
Components
  • Interleukin-12 subunit beta
  • Interleukin-23 subunit alpha
KeywordsCYTOKINE / heterodimer / EXTRACELLULAR / INFLAMMATION / FIBRONECTIN TYPE III
Function / homology
Function and homology information


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 / 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 ...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 / 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 / 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 mononuclear cell proliferation / interleukin-12 receptor binding / positive regulation of memory T cell differentiation / T-helper cell differentiation / natural killer cell activation / Interleukin-23 signaling / CD22 mediated BCR regulation / 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 / positive regulation of neutrophil chemotaxis / Interleukin-12 signaling / response to UV-B / positive regulation of natural killer cell proliferation / positive regulation of granulocyte macrophage colony-stimulating factor production / cytokine receptor activity / Fc epsilon receptor (FCERI) signaling / T-helper 1 type immune response / Classical antibody-mediated complement activation / negative regulation of interleukin-10 production / Initial triggering of complement / defense response to protozoan / positive regulation of activated T cell proliferation / cytokine binding / positive regulation of interleukin-17 production / Interleukin-10 signaling / immunoglobulin complex / cell surface receptor signaling pathway via JAK-STAT / positive regulation of interleukin-10 production / FCGR activation / negative regulation of protein secretion / Role of phospholipids in phagocytosis / Role of LAT2/NTAL/LAB on calcium mobilization / positive regulation of defense response to virus by host / Scavenging of heme from plasma / 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 / regulation of cytokine production / positive regulation of interleukin-12 production / antigen binding / positive regulation of cell adhesion / FCERI mediated Ca+2 mobilization / FCGR3A-mediated IL10 synthesis / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / Regulation of Complement cascade / cytokine activity / negative regulation of inflammatory response to antigenic stimulus / Cell surface interactions at the vascular wall / FCGR3A-mediated phagocytosis / FCERI mediated MAPK activation / negative regulation of smooth muscle cell proliferation / cellular response to type II interferon / cytokine-mediated signaling pathway / Regulation of actin dynamics for phagocytic cup formation / FCERI mediated NF-kB activation / 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 / Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell / 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 / blood microparticle / adaptive immune response / Potential therapeutics for SARS / receptor complex / inflammatory response / immune response / protein heterodimerization activity / endoplasmic reticulum lumen / external side of plasma membrane / innate immune response / protein-containing complex binding / positive regulation of transcription by RNA polymerase II / extracellular space
Similarity search - Function
Interleukin-23 alpha / Interleukin 23 subunit alpha / 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. / Four-helical cytokine-like, core / : ...Interleukin-23 alpha / Interleukin 23 subunit alpha / 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. / Four-helical cytokine-like, core / : / Immunoglobulin subtype 2 / Immunoglobulin C-2 Type / Immunoglobulin V-Type / Fibronectin type-III domain profile. / Fibronectin type III / Fibronectin type III superfamily / Immunoglobulin V-set domain / Immunoglobulin V-set domain / Immunoglobulin subtype / Immunoglobulin / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Immunoglobulin-like fold
Similarity search - Domain/homology
TERBIUM(III) ION / Interleukin-12 subunit beta / Immunoglobulin kappa variable 1-39
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsBloch, Y. / Savvides, S.N.
Funding support Belgium, 1items
OrganizationGrant numberCountry
Research Foundation - Flanders (FWO)12S0519N Belgium
Citation
Journal: 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.
#1: Journal: Acta Crystallogr D Biol Crystallogr / Year: 2012
Title: Towards automated crystallographic structure refinement with phenix.refine.
Authors: Afonine, P.V. / Grosse-Kunstleve, R.W. / Echols, N. / Headd, J.J. / Moriarty, N.W. / Mustyakimov, M. / Terwilliger, T.C. / Urzhumtsev, A. / Zwart, P.H. / Adams, P.D.
History
DepositionMar 8, 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 6, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Interleukin-12 subunit beta
B: Interleukin-23 subunit alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)59,5914
Polymers58,3592
Non-polymers1,2322
Water1,51384
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: light scattering, heterodimer has been observed multiple times in crystal structures and EM structures. Mass also measured on MALS.
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3600 Å2
ΔGint6 kcal/mol
Surface area23380 Å2
Unit cell
Length a, b, c (Å)67.748, 59.842, 69.989
Angle α, β, γ (deg.)90.000, 98.060, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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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 / NK ...IL-12B / Cytotoxic lymphocyte maturation factor 40 kDa subunit / CLMF p40 / IL-12 subunit p40 / NK cell stimulatory factor chain 2 / NKSF2


Mass: 36714.383 Da / Num. of mol.: 1 / Mutation: N303D
Source method: isolated from a genetically manipulated source
Details: Residues [1-17] encode a secretion signal that is most likely co-translationaly removed. Residues [18-19] encode a scar to mimic such found in pdb 3duh.
Source: (gene. exp.) Homo sapiens (human) / Gene: IL12B, NKSF2 / Plasmid: pHLsec / Cell line (production host): HEK293S / Production host: Homo sapiens (human) / References: UniProt: P29460
#2: Protein Interleukin-23 subunit alpha / IL-23 subunit alpha / IL-23-A / Interleukin-23 subunit p19 / IL-23p19


Mass: 21644.498 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: N-terminal MGWSCIILFLVATATGVHS encode the secretion signal which was most likely removed co-translationaly. Following SRN encode a cloning scar meant to mimick and improve upon the construct ...Details: N-terminal MGWSCIILFLVATATGVHS encode the secretion signal which was most likely removed co-translationaly. Following SRN encode a cloning scar meant to mimick and improve upon the construct of pdb 3duh. C-terminal HHHHHH encode the purification tag which wasn't removed.
Source: (gene. exp.) Homo sapiens (human) / Gene: IL23A, SGRF, UNQ2498/PRO5798 / Plasmid: pHLsec / Cell line (production host): HEK293S / Production host: Homo sapiens (human) / References: UniProt: Q9NPF7
#3: Polysaccharide alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-6)-[alpha-D-mannopyranose-(1-3)]beta-D- ...alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-6)-[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: 1072.964 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-2DManpa1-6[DManpa1-3]DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/3,6,5/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3-3-3/a4-b1_b4-c1_c3-d1_c6-e1_e2-f1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{}[(6+1)][a-D-Manp]{[(2+1)][a-D-Manp]{}}}}}LINUCSPDB-CARE
#4: Chemical ChemComp-TB / TERBIUM(III) ION


Mass: 158.925 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Tb
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 84 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestN
Has protein modificationY

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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: 2.7 Å3/Da / Density % sol: 54.44 %
Crystal growTemperature: 287 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: (Morpheus2 E7) 2mM Lanthanides, 0.1M BES/ TEA, 10% PEG8000,20% 1.5-pentanediol

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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: P14 (MX2) / Wavelength: 0.9763 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Aug 8, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
ReflectionResolution: 2→69.3 Å / Num. obs: 35521 / % possible obs: 94.3 % / Redundancy: 6.58 % / Biso Wilson estimate: 47 Å2 / CC1/2: 0.999 / Rrim(I) all: 0.073 / Net I/σ(I): 13.9
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Mean I/σ(I) obsNum. unique obsCC1/2Rrim(I) all% possible all
2.27-2.457.053.4152520.8980.55899.3
2.12-2.276.021.9153120.7610.89193.5
2-2.125.071.0244690.5161.41174.1

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
XDS20200131data reduction
XDS20200131data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2→69.3 Å / SU ML: 0.2991 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 30.8866
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2559 2011 5.66 %
Rwork0.235 33495 -
obs0.2362 35506 94.28 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 65.54 Å2
Refinement stepCycle: LAST / Resolution: 2→69.3 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3405 0 73 84 3562
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00273598
X-RAY DIFFRACTIONf_angle_d0.52514903
X-RAY DIFFRACTIONf_chiral_restr0.0402565
X-RAY DIFFRACTIONf_plane_restr0.0037617
X-RAY DIFFRACTIONf_dihedral_angle_d14.01991308
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2-2.050.37061010.38041708X-RAY DIFFRACTION67.78
2.05-2.110.35211060.341936X-RAY DIFFRACTION77.58
2.11-2.170.35161280.31972199X-RAY DIFFRACTION87.22
2.17-2.240.35691550.31612371X-RAY DIFFRACTION94.86
2.24-2.320.32011550.29012530X-RAY DIFFRACTION99.37
2.32-2.410.29311420.30922507X-RAY DIFFRACTION98.92
2.41-2.520.30381570.2922503X-RAY DIFFRACTION99.03
2.52-2.650.3161370.27242498X-RAY DIFFRACTION99.17
2.65-2.820.32541630.27322528X-RAY DIFFRACTION99.12
2.82-3.040.31281510.27212515X-RAY DIFFRACTION99.59
3.04-3.340.26071510.25542545X-RAY DIFFRACTION99.45
3.34-3.830.26231650.22152504X-RAY DIFFRACTION99.59
3.83-4.820.20521060.19382607X-RAY DIFFRACTION99.38
4.82-69.30.20531940.1982544X-RAY DIFFRACTION98.21
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)
12.962205965930.4824116978531.380640373863.309919586791.914366861233.3523981244-0.08884077620710.1295659863070.0617884671230.0341364939188-0.6114113108440.8524660928140.458166895453-1.17754915225-0.4295686703220.467449603323-0.0681037513550.01393747708220.85588100775-0.309974713630.565613856289-20.3117.8-0.652
25.590562757780.5496206996963.559775870142.333886515641.408031671265.36865572463-0.001597356797640.1815834331650.196151301483-0.0989604020641-0.1609293539630.155129125363-0.0370647155859-0.171745149217-0.00493578801670.29601292489-0.04049853779370.05084553989390.378612020263-0.0232230780210.364639061739-4.03233.72215.364
33.312933695021.301822064660.6289051798495.5287386710.02710276508993.67977451523-0.0236090904703-0.3352982852170.6501112249540.2693437798-0.1807947817890.440389818812-0.514808287778-0.2806406677410.02128405693030.4067865181370.05900519171820.03564170814010.422094140447-0.120636970190.50287605077910.81353.0133.363
46.24975670147-1.303157989390.1860716031044.555979654160.2221878954773.311862326150.161394794730.358212738392-0.345197698345-0.156155586346-0.220460120003-0.286700829890.06522935534960.099722266159-0.1513134764350.3355350662520.0539092484941-0.03909653146920.271863293314-0.0239447569440.35689505690825.5728.54428.26
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( CHAIN A AND ( RESID 21:110 OR RESID 401:401 ) )A21 - 110
2X-RAY DIFFRACTION1( CHAIN A AND ( RESID 21:110 OR RESID 401:401 ) )A401
3X-RAY DIFFRACTION2( CHAIN A AND RESID 111:232 )A111 - 232
4X-RAY DIFFRACTION3( CHAIN A AND RESID 233:328 )A233 - 328
5X-RAY DIFFRACTION4( CHAIN B AND RESID 27:189 )B27 - 189

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