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

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Basic information

Entry
Database: PDB / ID: 8odx
TitleInterleukin 12 receptor subunit beta-1 Fn domains in complex with antagonistic FAb4 fragment and VHH.
Components
  • FAb4 Heavy chain
  • FAb4 Light chain
  • Interleukin-12 receptor subunit beta-1
  • anti Kappa Light chain VHH
KeywordsCYTOKINE / receptor / fibronectin / antagonist
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)
Lama glama (llama)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 4.4 Å
AuthorsBloch, Y. / 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 9, 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 13, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Interleukin-12 receptor subunit beta-1
H: FAb4 Heavy chain
K: anti Kappa Light chain VHH
L: FAb4 Light chain


Theoretical massNumber of molelcules
Total (without water)110,9234
Polymers110,9234
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: homology, Complex same as observed in other crystal structures
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6560 Å2
ΔGint-31 kcal/mol
Surface area37880 Å2
Unit cell
Length a, b, c (Å)231.402, 231.402, 231.402
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number213
Space group name H-MP4132
Space group name HallP4bd2ab3
Symmetry operation#1: x,y,z
#2: x+1/4,-z+1/4,y+3/4
#3: x+3/4,z+1/4,-y+1/4
#4: z+3/4,y+1/4,-x+1/4
#5: -z+1/4,y+3/4,x+1/4
#6: -y+1/4,x+3/4,z+1/4
#7: y+1/4,-x+1/4,z+3/4
#8: z,x,y
#9: y,z,x
#10: -y+1/2,-z,x+1/2
#11: z+1/2,-x+1/2,-y
#12: -y,z+1/2,-x+1/2
#13: -z+1/2,-x,y+1/2
#14: -z,x+1/2,-y+1/2
#15: y+1/2,-z+1/2,-x
#16: x+1/2,-y+1/2,-z
#17: -x,y+1/2,-z+1/2
#18: -x+1/2,-y,z+1/2
#19: y+3/4,x+1/4,-z+1/4
#20: -y+3/4,-x+3/4,-z+3/4
#21: z+1/4,-y+1/4,x+3/4
#22: -z+3/4,-y+3/4,-x+3/4
#23: -x+1/4,z+3/4,y+1/4
#24: -x+3/4,-z+3/4,-y+3/4

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Components

#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: 40884.930 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: Residues [1-29] encode signaling peptide which is most likely removed co-translationaly. Residues [393-340] are cloning scar Residues [341-344] encode the caspase3 cleavage site. Residues ...Details: Residues [1-29] encode signaling peptide which is most likely removed co-translationaly. Residues [393-340] are cloning scar Residues [341-344] encode the caspase3 cleavage site. Residues [345-C] encode the AVI-His purification tag, no longer present as protein was treated with Caspase
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
#2: Antibody FAb4 Heavy chain


Mass: 26775.973 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: Residues [1-19] encode the signal peptide. Residues [244-C] the purification tag
Source: (gene. exp.) Homo sapiens x Mus musculus hybrid cell line (mammal)
Plasmid: pHLsec / Production host: Homo sapiens (human)
#3: Antibody anti Kappa Light chain VHH


Mass: 18058.037 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: Residues [1-24] encode pelB secretion signal. Residues [25-45] encode the purification tag and caspase cleavage site. Protein was digested with caspase.
Source: (gene. exp.) Lama glama (llama) / Plasmid: pET / Production host: Escherichia coli (E. coli) / Strain (production host): T7 Express lysY/Iq
#4: Antibody FAb4 Light chain


Mass: 25204.225 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: Residues [1-19] encode signal peptide, most likely cleaved of co-translationaly.
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)
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: 4.65 Å3/Da / Density % sol: 73.57 %
Crystal growTemperature: 287 K / Method: vapor diffusion, sitting drop / pH: 6.34
Details: 11.82% Tacsimate,10% Ethylene glycol,10 % PEG smear broad

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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: 0.915 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jun 4, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.915 Å / Relative weight: 1
ReflectionResolution: 4.4→231.4 Å / Num. obs: 13975 / % possible obs: 100 % / Redundancy: 70 % / Biso Wilson estimate: 246.09 Å2 / CC1/2: 1 / Rrim(I) all: 0.231 / Net I/σ(I): 18.54
Reflection shell

Diffraction-ID: 1 / % possible all: 100

Resolution (Å)Redundancy (%)Mean I/σ(I) obsNum. unique obsCC1/2Rrim(I) all
4.4-4.6771.361.3621930.5683.941
4.67-4.9972.392.6920740.8322.376
4.99-5.3972.44.519440.9271.5
5.39-5.9171.216.417900.9591.077

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Processing

Software
NameVersionClassification
BUSTERrefinement
PHENIX1.20.1_4487refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 4.4→81.81 Å / SU ML: 0.8081 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 35.6637
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.3115 1396 10 %
Rwork0.2796 12568 -
obs0.2827 13964 99.94 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 270.41 Å2
Refinement stepCycle: LAST / Resolution: 4.4→81.81 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6382 0 0 0 6382
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00456537
X-RAY DIFFRACTIONf_angle_d0.82378898
X-RAY DIFFRACTIONf_chiral_restr0.0501984
X-RAY DIFFRACTIONf_plane_restr0.00551145
X-RAY DIFFRACTIONf_dihedral_angle_d12.2482327
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
4.4-4.560.45731360.44861227X-RAY DIFFRACTION100
4.56-4.740.45471350.38681216X-RAY DIFFRACTION99.93
4.74-4.960.34981380.34641238X-RAY DIFFRACTION100
4.96-5.220.3531360.33271222X-RAY DIFFRACTION100
5.22-5.550.33531370.34771235X-RAY DIFFRACTION100
5.55-5.970.42151370.36081235X-RAY DIFFRACTION100
5.98-6.580.33811400.30991261X-RAY DIFFRACTION100
6.58-7.530.37041400.31061265X-RAY DIFFRACTION100
7.53-9.480.25621430.23191279X-RAY DIFFRACTION100
9.49-81.810.26621540.23341390X-RAY DIFFRACTION99.55
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)
19.04796212974-0.717230804533-0.09657762978599.268968674021.688096028785.61551669542-0.510001956543-1.20541612209-0.8575287248792.826971627660.575367911626-1.099047963371.296474206331.48028686770.8607169183031.825855778120.260765617798-0.1204142563182.04951571808-0.1623053133891.85962029202-50.979540055340.979555832631.899532159
22.09291750127-3.33128536423-1.103059374071.769227737637.072518283447.21881546961-0.785630036273-0.621061946927-0.6425098259571.597545973430.1047364950650.6202082350341.88019724410.31795280989-1.66976426019E-72.562833877210.5193270728780.389903089012.546643310080.2086861322532.80791355913-73.895781748150.279003086828.6152283028
30.5014772529050.6039965184792.223760546585.0431684253.07414154285.33647436651-1.083681636520.2351628053580.05422696251920.815689580224-0.4565869303690.324487317953-0.540334289357-0.6155957855058.95915040314E-83.54282232270.758080635216-0.1579221640212.83149492143-0.02558356705372.57331623008-88.651703109167.863475972153.1104027121
45.6241072986-3.574602046832.1665820976213.35520102072.775093431093.79542164526-0.1053224984950.189865887641-0.0912080663207-1.897675716420.090829697903-0.7025426462330.6215924993410.329519573734-1.77766274744E-53.07266182764-1.246868675260.4591636606773.2496065893-0.2947982397231.72524991937-46.728664609712.0951748691-21.8749487273
53.16910854536-2.19992464804-0.8881727363555.344421926-1.200193061822.65631126923-0.3462223621930.9448310158230.951082724230.5110238797720.31487268255-0.142098688111-0.151410630323-0.612248515628-1.41945308947E-82.6514459022-0.0560294830533-0.1510967144432.90257628171-0.2823613735173.14241288814-39.24009976454.34253362938.59680938476
62.88557998996-0.455796060812-2.12964068835.247410068530.7900333697343.463108738050.1365409238150.2404657584761.78511333824-0.741389910709-1.138921676270.384033440273-0.247024806575-1.700814356975.74625134554E-82.16264591293-0.198789482171-0.04973343877073.103937995920.2734805730762.97883078186-33.556122647750.0811978421-27.0393227817
77.07624561691-2.62945819722-3.407463684424.03908347643-4.076223731162.21350888325-0.601697611037-1.070115925870.7695884146650.976219664220.575709792277-0.5158460573210.376980993124-1.787862082611.226595932281.58812248467-0.2336521854780.1241544122652.49332741722-0.1810101003521.85194062061-49.991517095535.40525955853.43746794795
8-1.517678938973.53407249629-0.6402591555420.375987541508-5.740587944552.70771604563-1.000870973850.5853529518990.107585717951-1.94280938880.128864312031-0.6499811503330.939599292045-0.631858521329-5.68422452313E-82.97750117576-0.4099600020890.6564251705613.061162698410.02790531990313.01244376994-29.193203880134.6608491841-25.3205326941
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsLabel asym-IDLabel seq-ID
1X-RAY DIFFRACTION1{ A|239-342 }A1 - 85
2X-RAY DIFFRACTION2{ A|343-442 }A86 - 185
3X-RAY DIFFRACTION3{ A|443-539 }A186 - 282
4X-RAY DIFFRACTION4{ K|1-120 }C1 - 120
5X-RAY DIFFRACTION5{ H|2-122 }B1 - 121
6X-RAY DIFFRACTION6{ H|123-221 }B122 - 220
7X-RAY DIFFRACTION7{ L|1-106 }D1 - 106
8X-RAY DIFFRACTION8{ L|107-212 }D107 - 212

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