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- PDB-8c7m: Interleukin 12 receptor subunit beta-1 Fn domains in complex with... -

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Basic information

Entry
Database: PDB / ID: 8c7m
TitleInterleukin 12 receptor subunit beta-1 Fn domains in complex with antagonistic FAb fragment.
Components
  • FAb4 Crystal Kappa Light chain
  • FAb4 Heavy chain
  • Interleukin-12 receptor subunit beta-1
KeywordsCYTOKINE / receptor / antagonist / antibody
Function / homology
Function and homology information


positive regulation of T-helper 1 type immune response / interleukin-12 receptor complex / interleukin-23 receptor complex / positive regulation of memory T cell differentiation / interleukin-23-mediated signaling pathway / Interleukin-23 signaling / positive regulation of T-helper 17 type immune response / interleukin-12-mediated signaling pathway / Interleukin-12 signaling / cytokine receptor activity ...positive regulation of T-helper 1 type immune response / interleukin-12 receptor complex / interleukin-23 receptor complex / positive regulation of memory T cell differentiation / interleukin-23-mediated signaling pathway / Interleukin-23 signaling / positive regulation of T-helper 17 type immune response / interleukin-12-mediated signaling pathway / Interleukin-12 signaling / cytokine receptor activity / cytokine binding / positive regulation of activated T cell proliferation / positive regulation of T-helper 17 cell lineage commitment / coreceptor activity / positive regulation of defense response to virus by host / cellular response to type II interferon / positive regulation of T cell mediated cytotoxicity / positive regulation of type II interferon production / cytokine-mediated signaling pathway / receptor complex / external side of plasma membrane / positive regulation of cell population proliferation / signal transduction / plasma membrane
Similarity search - Function
Long hematopoietin receptor, Gp130 family 2, conserved site / Long hematopoietin receptor, gp130 family signature. / Fibronectin type III domain / Fibronectin type 3 domain / Fibronectin type-III domain profile. / Fibronectin type III / Fibronectin type III superfamily / Immunoglobulin-like fold
Similarity search - Domain/homology
Interleukin-12 receptor subunit beta-1
Similarity search - Component
Biological speciesHomo sapiens (human)
Homo sapiens x Mus musculus hybrid cell line (mammal)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.56 Å
AuthorsBloch, Y. / Savvides, S.N.
Funding support Belgium, 2items
OrganizationGrant numberCountry
Research Foundation - Flanders (FWO)G0B4918N Belgium
Research Foundation - Flanders (FWO)12S0519N 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
DepositionJan 16, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 31, 2024Provider: repository / Type: Initial release
Revision 1.1Feb 7, 2024Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2May 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 1.3Oct 9, 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

Downloads & links

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Assembly

Deposited unit
A: Interleukin-12 receptor subunit beta-1
B: Interleukin-12 receptor subunit beta-1
C: FAb4 Heavy chain
D: FAb4 Crystal Kappa Light chain
H: FAb4 Heavy chain
L: FAb4 Crystal Kappa Light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)165,74213
Polymers164,5656
Non-polymers1,1777
Water43224
1
A: Interleukin-12 receptor subunit beta-1
H: FAb4 Heavy chain
L: FAb4 Crystal Kappa Light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)83,2389
Polymers82,2833
Non-polymers9566
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Interleukin-12 receptor subunit beta-1
C: FAb4 Heavy chain
D: FAb4 Crystal Kappa Light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)82,5044
Polymers82,2833
Non-polymers2211
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)73.663, 140.178, 219.363
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Antibody , 2 types, 4 molecules CHDL

#2: Antibody FAb4 Heavy chain


Mass: 24786.586 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: [225-231] encode cloning scar and 6His tag
Source: (gene. exp.) Homo sapiens x Mus musculus hybrid cell line (mammal)
Plasmid: pHLsec / Cell line (production host): HEK293S / Production host: Homo sapiens (human)
#3: Antibody FAb4 Crystal Kappa Light chain


Mass: 23239.732 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens x Mus musculus hybrid cell line (mammal)
Plasmid: pHLsec / Cell line (production host): HEK293S MGAT1-/- / Production host: Homo sapiens (human)

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Protein / Sugars , 2 types, 7 molecules AB

#1: 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: 34256.363 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: [310-314] encode a protease site / Source: (gene. exp.) Homo sapiens (human) / Gene: IL12RB1, IL12R, IL12RB / Plasmid: pHLsec / Cell line (production host): HEK293S MGAT1-/- / Production host: Homo sapiens (human) / References: UniProt: P42701
#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.: 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 , 2 types, 26 molecules

#5: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 24 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 3.44 Å3/Da / Density % sol: 64.26 %
Crystal growTemperature: 287 K / Method: vapor diffusion, sitting drop
Details: Morpheus2 condition A3: 90 mM LiNaKSO4, 100 mM Citrate BisTRIS propane pH 5.4, 8.57% PEG 8000, 17.14% 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 16, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
ReflectionResolution: 2.56→140.18 Å / Num. obs: 73952 / % possible obs: 99.8 % / Redundancy: 13.6 % / Biso Wilson estimate: 76.27 Å2 / CC1/2: 0.999 / Rrim(I) all: 0.104 / Net I/σ(I): 19.16
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Mean I/σ(I) obsNum. unique obsCC1/2Rrim(I) all% possible all
7.66-140.1812.4265.9430020.9990.03899.8
5.43-7.6613.52649.2851600.9990.048100
4.43-5.4313.379947.4965750.9990.04899.9
3.84-4.4313.5533.9677150.9990.07199.9
3.43-3.8413.8920.8586980.9970.13199.9
3.13-3.4313.778411.3295970.9890.255100
2.9-3.1313.76685.37103890.9530.5699.9
2.71-2.913.922.65111100.8371.124100
2.56-2.7113.2851.3117060.5662.08398.9

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Processing

Software
NameVersionClassification
PHENIX(1.20.1_4487: ???)refinement
XDS20210323data reduction
XDS20210323data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.56→70.09 Å / SU ML: 0.38 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 25.35 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2282 1999 2.7 %
Rwork0.2034 --
obs0.2041 73930 99.75 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.56→70.09 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10815 0 72 24 10911
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00311148
X-RAY DIFFRACTIONf_angle_d0.56415184
X-RAY DIFFRACTIONf_dihedral_angle_d12.1653973
X-RAY DIFFRACTIONf_chiral_restr0.0441714
X-RAY DIFFRACTIONf_plane_restr0.0051934
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.56-2.620.38381370.35464958X-RAY DIFFRACTION97
2.62-2.690.32851420.30835081X-RAY DIFFRACTION100
2.69-2.770.3621400.2855058X-RAY DIFFRACTION100
2.77-2.860.29381420.28525096X-RAY DIFFRACTION100
2.86-2.970.31281420.29735106X-RAY DIFFRACTION100
2.97-3.080.33851410.29285102X-RAY DIFFRACTION100
3.08-3.230.27911420.2555115X-RAY DIFFRACTION100
3.23-3.40.25361420.22975089X-RAY DIFFRACTION100
3.4-3.610.27151420.22555123X-RAY DIFFRACTION100
3.61-3.890.26461440.22425169X-RAY DIFFRACTION100
3.89-4.280.23171440.17315154X-RAY DIFFRACTION100
4.28-4.90.15751430.1435177X-RAY DIFFRACTION100
4.9-6.170.17221460.16555249X-RAY DIFFRACTION100
6.17-70.090.1961520.18835454X-RAY DIFFRACTION100
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)
15.6888-0.99080.50384.28042.65333.98940.0883-0.280.6048-0.05480.1085-0.2249-0.38880.2779-0.23740.75-0.08750.18850.4718-0.23260.816618.212986.989436.7152
22.70283.201-0.0564.80152.13616.4386-0.38330.2885-0.20810.06280.2326-0.23670.17920.06810.120.8314-0.00350.18040.60970.15050.7785-0.834426.330566.4485
33.5981.32750.97782.77840.74561.72970.2057-1.7153-0.11950.7594-0.4049-0.16640.23950.0790.20391.1418-0.05950.10561.44470.0320.66878.415443.285489.825
43.5288-0.8929-0.11224.9235-1.0656.15960.1272-0.90750.98861.30160.2575-0.3785-1.5242-0.0879-0.17952.0178-0.127-0.23481.6498-0.25031.159533.241168.328998.8784
55.47682.3522-0.39863.4305-0.60073.4225-0.1559-0.45590.01180.22950.2112-0.2457-0.2020.3089-0.04490.80350.01660.02690.7033-0.13550.682819.715248.339470.67
61.81251.4785-0.62182.5065-1.22360.59720.1412-0.8714-0.26151.0751-0.2135-0.5752-0.64340.89190.05451.6313-0.1005-0.35031.6334-0.28231.323344.842559.185493.1747
74.6874-1.71230.4993.3706-2.83675.2713-0.14330.246-0.14150.12070.38-0.20680.0836-0.0346-0.21510.7985-0.05470.16930.613-0.28510.760915.898274.054559.0548
82.3619-2.0552-3.41971.4543.29296.7608-0.2876-0.0737-0.34690.14260.09170.02650.4608-0.09120.19110.8259-0.10820.1120.6388-0.1890.7815.96580.122174.1544
96.00011.3170.47635.49271.60963.7194-0.14580.78731.30320.30330.13050.6844-0.5138-0.05050.13111.00850.03040.15160.83430.32791.1497-17.635143.936256.7761
106.353-0.50311.81961.57080.02543.9839-0.00980.75120.3113-0.1226-0.11080.6632-0.1202-1.54430.15550.99230.03080.12721.5430.19961.1976-35.389439.658653.207
112.5510.40990.27893.36061.35776.08290.2022-0.26130.46840.149-0.14510.399-0.44250.006-0.03360.4340.02460.08110.3931-0.10970.613410.069865.000420.0924
122.993-1.199-0.2594.2554-0.08582.5213-0.2058-0.1782-0.16730.01150.07290.1010.14280.09670.1310.2901-0.0225-0.020.4194-0.03950.375520.333735.55724.5211
133.1435-1.54460.03724.29870.31982.74490.1898-0.15690.39190.25480.0658-0.374-0.24120.7427-0.23470.5913-0.0860.04630.7633-0.27660.626631.585664.111824.4966
145.8251-0.13651.06112.33920.60556.8572-0.1411-0.12220.2028-0.08170.0949-0.0829-0.1711-0.06920.04660.32630.0392-0.00970.3010.00420.439133.412140.4396-3.3041
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain A and resid 238:341
2X-RAY DIFFRACTION2chain B and resid 238:342
3X-RAY DIFFRACTION3chain C and resid 2:126
4X-RAY DIFFRACTION4chain C and resid 127:221
5X-RAY DIFFRACTION5chain D and resid 1:111
6X-RAY DIFFRACTION6chain D and resid 112:210
7X-RAY DIFFRACTION7chain A and resid 342:382
8X-RAY DIFFRACTION8chain A and resid 383:540
9X-RAY DIFFRACTION9chain B and resid 343:380
10X-RAY DIFFRACTION10chain B and resid 381:539
11X-RAY DIFFRACTION11chain H and resid 1:117
12X-RAY DIFFRACTION12chain H and resid 118:222
13X-RAY DIFFRACTION13chain L and resid 0:106
14X-RAY DIFFRACTION14chain L and resid 107:210

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