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- PDB-6wdq: IL23/IL23R/IL12Rb1 signaling complex -

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Basic information

Entry
Database: PDB / ID: 6wdq
TitleIL23/IL23R/IL12Rb1 signaling complex
Components
  • (Interleukin-12 ...Interleukin 12) x 2
  • (Interleukin-23 ...Interleukin 23) x 2
KeywordsSIGNALING PROTEIN / cytokine receptor
Function / homology
Function and homology information


late endosome lumen / interleukin-23 receptor binding / interleukin-23-mediated signaling pathway / interleukin-12 alpha subunit binding / interleukin-12 complex / interleukin-23 complex / regulation of tyrosine phosphorylation of STAT protein / 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 ...late endosome lumen / interleukin-23 receptor binding / interleukin-23-mediated signaling pathway / interleukin-12 alpha subunit binding / interleukin-12 complex / interleukin-23 complex / regulation of tyrosine phosphorylation of STAT protein / 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 tissue remodeling / positive regulation of lymphocyte proliferation / positive regulation of activation of Janus kinase activity / tissue remodeling / sexual reproduction / positive regulation of smooth muscle cell apoptotic process / positive regulation of T-helper 1 type immune response / positive regulation of NK T cell activation / positive regulation of mononuclear cell proliferation / positive regulation of T-helper 17 cell lineage commitment / interleukin-12 receptor binding / positive regulation of memory T cell differentiation / natural killer cell activation / T-helper cell differentiation / interleukin-12 receptor complex / interleukin-23 receptor complex / negative regulation of interleukin-17 production / positive regulation of osteoclast differentiation / Interleukin-23 signaling / positive regulation of T-helper 17 type immune response / positive regulation of NK T cell proliferation / interleukin-12-mediated signaling pathway / positive regulation of neutrophil chemotaxis / positive regulation of granulocyte macrophage colony-stimulating factor production / Interleukin-12 signaling / response to UV-B / cytokine receptor activity / positive regulation of natural killer cell activation / T-helper 1 type immune response / negative regulation of interleukin-10 production / cytokine binding / positive regulation of activated T cell proliferation / response to type II interferon / defense response to protozoan / positive regulation of interleukin-17 production / Interleukin-10 signaling / positive regulation of natural killer cell proliferation / positive regulation of interleukin-10 production / negative regulation of protein secretion / positive regulation of cell adhesion / T cell proliferation / positive regulation of tyrosine phosphorylation of STAT protein / regulation of cytokine production / negative regulation of inflammatory response to antigenic stimulus / positive regulation of defense response to virus by host / positive regulation of T cell proliferation / positive regulation of interleukin-12 production / cytokine activity / negative regulation of smooth muscle cell proliferation / positive regulation of inflammatory response / positive regulation of T cell mediated cytotoxicity / cellular response to type II interferon / cytokine-mediated signaling pathway / positive regulation of non-canonical NF-kappaB signal transduction / cell migration / positive regulation of type II interferon production / positive regulation of tumor necrosis factor production / defense response to virus / Interleukin-4 and Interleukin-13 signaling / cellular response to lipopolysaccharide / defense response to Gram-negative bacterium / response to lipopolysaccharide / receptor complex / inflammatory response / protein heterodimerization activity / endoplasmic reticulum lumen / external side of plasma membrane / innate immune response / protein-containing complex binding / signal transduction / positive regulation of transcription by RNA polymerase II / extracellular space / extracellular region / identical protein binding / plasma membrane / cytosol
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. / Long hematopoietin receptor, Gp130 family 2, conserved site / Long hematopoietin receptor, gp130 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. / 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 beta / Interleukin-12 receptor subunit beta-1 / Interleukin-23 receptor / Interleukin-23 subunit alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.4 Å
AuthorsJude, K.M. / Ely, L.K. / Glassman, C.R. / Thomas, C. / Spangler, J.B. / Lupardus, P.J. / Garcia, K.C.
Funding support1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)5R01CA177684
CitationJournal: Cell / Year: 2021
Title: Structural basis for IL-12 and IL-23 receptor sharing reveals a gateway for shaping actions on T versus NK cells.
Authors: Caleb R Glassman / Yamuna Kalyani Mathiharan / Kevin M Jude / Leon Su / Ouliana Panova / Patrick J Lupardus / Jamie B Spangler / Lauren K Ely / Christoph Thomas / Georgios Skiniotis / K Christopher Garcia /
Abstract: Interleukin-12 (IL-12) and IL-23 are heterodimeric cytokines that are produced by antigen-presenting cells to regulate the activation and differentiation of lymphocytes, and they share IL-12Rβ1 as a ...Interleukin-12 (IL-12) and IL-23 are heterodimeric cytokines that are produced by antigen-presenting cells to regulate the activation and differentiation of lymphocytes, and they share IL-12Rβ1 as a receptor signaling subunit. We present a crystal structure of the quaternary IL-23 (IL-23p19/p40)/IL-23R/IL-12Rβ1 complex, together with cryoelectron microscopy (cryo-EM) maps of the complete IL-12 (IL-12p35/p40)/IL-12Rβ2/IL-12Rβ1 and IL-23 receptor (IL-23R) complexes, which reveal "non-canonical" topologies where IL-12Rβ1 directly engages the common p40 subunit. We targeted the shared IL-12Rβ1/p40 interface to design a panel of IL-12 partial agonists that preserved interferon gamma (IFNγ) induction by CD8 T cells but impaired cytokine production from natural killer (NK) cells in vitro. These cell-biased properties were recapitulated in vivo, where IL-12 partial agonists elicited anti-tumor immunity to MC-38 murine adenocarcinoma absent the NK-cell-mediated toxicity seen with wild-type IL-12. Thus, the structural mechanism of receptor sharing used by IL-12 family cytokines provides a protein interface blueprint for tuning this cytokine axis for therapeutics.
History
DepositionApr 1, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 24, 2021Provider: repository / Type: Initial release
Revision 1.1Mar 3, 2021Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2May 5, 2021Group: Database references / Category: pdbx_related_exp_data_set
Revision 1.3Oct 18, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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
D: Interleukin-12 receptor subunit beta-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)116,49311
Polymers114,3774
Non-polymers2,1177
Water181
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration, microscopy, Structure imaged at low resolution by cryo-electron microscopy
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8310 Å2
ΔGint-3 kcal/mol
Surface area44920 Å2
Unit cell
Length a, b, c (Å)75.712, 118.483, 186.151
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP22121
Space group name HallP22ab(z,x,y)
Symmetry operation#1: x,y,z
#2: x,-y,-z
#3: -x,y+1/2,-z+1/2
#4: -x,-y+1/2,z+1/2

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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: 34910.152 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IL12B, NKSF2 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P29460
#4: Protein Interleukin-12 receptor subunit beta-1 / / IL-12RB1 / IL-12 receptor beta component


Mass: 24697.369 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: Trichoplusia ni (cabbage looper) / References: UniProt: P42701

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

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


Mass: 19099.559 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IL23A, SGRF, UNQ2498/PRO5798 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q9NPF7
#3: Protein Interleukin-23 receptor / / IL-23R


Mass: 35669.434 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IL23R / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q5VWK5

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Sugars , 3 types, 7 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-Glycam 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
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-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-Glycam 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
[]{[(4+1)][b-D-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 / N-Acetylglucosamine


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 5
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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Non-polymers , 1 types, 1 molecules

#8: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 3.69 Å3/Da / Density % sol: 66.64 %
Crystal growTemperature: 295 K / Method: vapor diffusion / pH: 9.4 / Details: PEG 12000 CAPSO pH 9.4 5% dioxane 10% spermine HCl

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: May 23, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.4→47.99 Å / Num. obs: 21806 / % possible obs: 89.67 % / Redundancy: 2.7 % / Biso Wilson estimate: 146.45 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.07234 / Rpim(I) all: 0.0506 / Rrim(I) all: 0.0888 / Net I/σ(I): 8.59
Reflection shellResolution: 3.4→3.522 Å / Redundancy: 2.7 % / Rmerge(I) obs: 2.118 / Mean I/σ(I) obs: 0.57 / Num. unique obs: 2240 / CC1/2: 0.286 / Rpim(I) all: 1.484 / Rrim(I) all: 2.602 / % possible all: 75.95

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5mzv, D_1000248020

5mzv


Resolution: 3.4→47.99 Å / SU ML: 0.6127 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 34.2933
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflectionSelection details
Rfree0.2946 1948 9.15 %random
Rwork0.2379 19350 --
obs0.243 21298 89.72 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 156.91 Å2
Refinement stepCycle: LAST / Resolution: 3.4→47.99 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6707 0 137 1 6845
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00257013
X-RAY DIFFRACTIONf_angle_d0.55759543
X-RAY DIFFRACTIONf_chiral_restr0.04611081
X-RAY DIFFRACTIONf_plane_restr0.00411206
X-RAY DIFFRACTIONf_dihedral_angle_d9.4889978
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.4-3.490.42611000.42641030X-RAY DIFFRACTION67.79
3.49-3.580.38371440.35751451X-RAY DIFFRACTION95.85
3.58-3.690.3961450.34431435X-RAY DIFFRACTION95.87
3.69-3.80.39741460.34421442X-RAY DIFFRACTION94.02
3.8-3.940.37681460.32871437X-RAY DIFFRACTION94.9
3.94-4.10.36421440.28821424X-RAY DIFFRACTION94.06
4.1-4.280.30511420.24881412X-RAY DIFFRACTION92.78
4.28-4.510.28061460.22531438X-RAY DIFFRACTION94.17
4.51-4.790.26131430.22091423X-RAY DIFFRACTION92.99
4.79-5.160.28641430.21711419X-RAY DIFFRACTION92.04
5.16-5.680.28571400.2051385X-RAY DIFFRACTION89.55
5.68-6.50.26751410.23131392X-RAY DIFFRACTION89.6
6.5-8.180.28151370.22951355X-RAY DIFFRACTION85.99
8.18-47.990.26371310.20081307X-RAY DIFFRACTION77.9
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)
12.53416413222-1.270659017791.254729934382.59477522892-2.536986731415.49807016858-0.409292353607-0.100701910746-0.167985290393-0.03067575502180.265713730019-0.006025454812250.6926866049350.06825423951860.1888994545031.17856972234-0.01748800171090.08198486637550.745347123341-0.1173664545130.960225444676-11.327375788922.8404989561-33.9896226578
23.087462645060.3355994434940.7418950420764.001199011072.79528833452.65595620185-0.3976028134710.314541650004-0.2216367403990.0492496961276-0.03902989564670.615512658871-0.640647882509-0.914202043820.4464484313550.915189432808-0.171761559794-0.004590466045121.1386984880.003024520512291.30109314853-36.985541420941.4503739185-36.8162941286
31.07658478002-1.680249950820.332612063585.306031685550.4232780627831.24013618352-0.00668422407657-0.1362169382240.02685661712770.190621460459-0.1456128413110.31538501809-0.118862647224-0.2235243057260.1915892347971.032546105120.001596047935540.05059760768291.01791367409-0.09492041615220.955808722561-35.460602896376.5016904994-10.4635839913
42.15449802908-0.989498216904-1.098670821251.77725349024-0.556785237662.873611079530.0793576544065-0.7252927454350.1815119825940.1811396209090.153435542664-0.389354513908-0.517531444165-0.179120650537-0.24104292972.048733764790.488544828106-0.2666463466281.50510817529-0.2208797693661.5377937118120.590262788417.1967707045-17.0277593056
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1(chain A)
2X-RAY DIFFRACTION2(chain B)
3X-RAY DIFFRACTION3(chain C)
4X-RAY DIFFRACTION4(chain D)

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