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- PDB-6wdp: Interleukin 12 receptor subunit beta-1 -

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Basic information

Entry
Database: PDB / ID: 6wdp
TitleInterleukin 12 receptor subunit beta-1
ComponentsInterleukin-12 receptor subunit beta-1
KeywordsSIGNALING PROTEIN / cytokine receptor
Function / homology
Function and homology information


interleukin-23-mediated signaling pathway / positive regulation of T-helper 1 type immune response / positive regulation of memory T cell differentiation / interleukin-12 receptor complex / interleukin-23 receptor complex / Interleukin-23 signaling / positive regulation of T-helper 17 type immune response / interleukin-12-mediated signaling pathway / Interleukin-12 signaling / cytokine receptor activity ...interleukin-23-mediated signaling pathway / positive regulation of T-helper 1 type immune response / positive regulation of memory T cell differentiation / interleukin-12 receptor complex / interleukin-23 receptor complex / 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 / positive regulation of defense response to virus by host / cytokine-mediated signaling pathway / cellular response to type II interferon / positive regulation of T cell mediated cytotoxicity / positive regulation of type II interferon production / receptor complex / external side of plasma membrane / 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)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MAD / Resolution: 2.01 Å
AuthorsSpangler, J.B. / Thomas, C. / Jude, K.M. / 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 1.2Dec 1, 2021Group: Database references / Category: database_2 / pdbx_related_exp_data_set
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 receptor subunit beta-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,0705
Polymers24,6971
Non-polymers3724
Water70339
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)55.780, 55.780, 182.010
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number96
Space group name H-MP43212
Space group name HallP4nw2abw
Symmetry operation#1: x,y,z
#2: -y+1/2,x+1/2,z+3/4
#3: y+1/2,-x+1/2,z+1/4
#4: x+1/2,-y+1/2,-z+1/4
#5: -x+1/2,y+1/2,-z+3/4
#6: -x,-y,z+1/2
#7: y,x,-z
#8: -y,-x,-z+1/2

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Components

#1: 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
#2: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 39 / 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: 2

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Sample preparation

Crystal
IDDensity Matthews (Å3/Da)Density % sol (%)
13.0159.11
2
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 5.9
Details: 1.75 M ammonium sulfate, 0.2 M NaCl, and 0.1 M sodium cacodylate pH 5.9

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Data collection

Diffraction
IDMean temperature (K)Crystal-IDSerial crystal experiment
11001N
21002N
31002N
41002N
Diffraction source
SourceSiteBeamlineIDWavelength (Å)
SYNCHROTRONALS 8.2.211
SYNCHROTRONSSRL BL12-220.9792
SYNCHROTRONSSRL BL12-230.9184
SYNCHROTRONSSRL BL12-240.9798
Detector
TypeIDDetectorDate
ADSC QUANTUM 315r1CCDSep 9, 2011
DECTRIS PILATUS 6M2PIXELJan 22, 2012
DECTRIS PILATUS 6M3PIXELJan 22, 2012
DECTRIS PILATUS 6M4PIXELJan 22, 2012
Radiation
IDProtocolMonochromatic (M) / Laue (L)Scattering typeWavelength-ID
1SINGLE WAVELENGTHMx-ray1
2MADMx-ray2
3MADMx-ray3
4MADMx-ray4
Radiation wavelength
IDWavelength (Å)Relative weight
111
20.97921
30.91841
40.97981
Reflection

Entry-ID: 6WDP

Resolution (Å)Num. obs% possible obs (%)Redundancy (%)Biso Wilson estimate (Å2)CC1/2Rmerge(I) obsRpim(I) allRrim(I) allDiffraction-IDNet I/σ(I)
2.01-36.191986998.841140.960.9990.10330.0320.1084113.8
2.5-47.41061999.912.40.9990.0670.0270.073226.3
2.5-47.41061899.712.40.9990.0730.030.079325.4
2.5-47.41063899.912.410.0690.0280.074226.3
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allDiffraction-ID% possible all
2.01-2.08291.6851.1618610.4380.58141.789194.03
2.5-2.612.80.843.111590.8240.3410.908299.4
2.5-2.612.50.9642.711520.7610.3981.044398.7
2.5-2.612.90.9672.711610.7830.3911.044299.6

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
XDSdata reduction
autoSHARPphasing
XDSdata scaling
RefinementMethod to determine structure: MAD / Resolution: 2.01→36.19 Å / SU ML: 0.2716 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 25.5969
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2417 994 5.01 %
Rwork0.2219 18850 -
obs0.223 19844 98.53 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 50.04 Å2
Refinement stepCycle: LAST / Resolution: 2.01→36.19 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1645 0 23 39 1707
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00441712
X-RAY DIFFRACTIONf_angle_d0.71962330
X-RAY DIFFRACTIONf_chiral_restr0.0426239
X-RAY DIFFRACTIONf_plane_restr0.0052307
X-RAY DIFFRACTIONf_dihedral_angle_d17.0452626
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.01-2.110.33231310.32172460X-RAY DIFFRACTION92.67
2.11-2.240.31021380.27452623X-RAY DIFFRACTION98.22
2.24-2.420.31731420.25912682X-RAY DIFFRACTION99.96
2.42-2.660.25171420.23872701X-RAY DIFFRACTION100
2.66-3.050.24081430.23012716X-RAY DIFFRACTION100
3.05-3.840.23081450.20032752X-RAY DIFFRACTION99.9
3.84-36.190.21771530.20622916X-RAY DIFFRACTION98.78
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)
12.71460299638-1.35623966032-0.09787013941664.81157219209-0.9637358746442.32343958032-0.241897982748-0.5848839630630.1131959586240.4396313647460.0823187452647-0.202903390428-0.08810832764210.09388926321650.04921047163530.4839146829920.03188546622370.0334491799750.443475739524-0.0243251090910.412814418067-22.853089413843.599604631630.5813965087
22.79156897997-0.873714266847-1.464006654983.921557367212.871397817934.16374205488-0.219513894866-0.0881594235695-0.1819430379410.591898113509-0.01283825194550.7053628103060.171576928754-0.1254473434720.2000495406690.4320297296990.0500420242170.07857804449020.3020390839030.08234095726460.36908642321-29.540153781932.741434207426.3348336175
32.69028794062-0.512189499035-1.373014640193.608301090141.007530297491.264849846850.0014348264006-0.315533980520.0387160491860.5218434838470.1198107600830.154914418323-0.0843591347416-0.042757829355-0.1277469415050.3665296006550.04431568520740.04168274206620.2960603725770.07415853773520.239259944864-23.230619100535.91097059624.6950235247
42.201879399722.89650369943-1.816042108554.26105822965-1.89776516291.90866903173-0.08105766288960.4378080408320.78470141439-0.4877541044310.5410140432330.4463980531620.101256355574-0.27448306188-0.4519831339060.39952938896-0.05137204962690.03125008801440.3263809081920.106112612380.53936093638-34.17306577958.411098550624.3647467079
52.08069740254-0.3003765609991.124275675570.9080563471530.4226042867962.02702880744-0.3408417391970.4515185625750.269167922141-0.701553310061-0.0456680933925-0.6771881777570.4925172786660.1599878995760.6930483240740.395402091427-0.03042081062330.07366998989180.4192927957920.1285653247540.548489274452-31.86581314486.0369418718222.0361167449
66.679096993241.86350295980.7666776209164.14560092363-3.058236912924.129269499640.0769034491677-0.5033751131530.8658610501640.101845809946-0.311131734455-0.418049697415-0.08773890904750.5940081348260.1859246736610.352834720389-0.05543313061150.08280533260710.250098539685-0.03755464757320.493304486784-31.13088890167.8846475590432.641935841
70.9834907491171.46076199543-0.19121696582.94888809232-1.167771075580.9008398423760.541378480080.09315633777881.287616640740.211504103455-0.2450061316760.374728168608-0.2050809550770.388230892826-0.1173624602580.477904731651-0.01041708280320.0471494662660.4178726968350.05556551300851.01252463082-27.551765303517.657172560725.8352335687
83.367209405831.70329921422-3.399025299411.7182914307-1.616532699873.411909823190.196972877298-0.4863453089710.00870436071322-0.023458358768-0.5493424605860.3571269142330.5677843786940.6542001470020.3100598111090.4500584224520.02497182956250.0287454155540.4591093098760.01806786311260.315583090835-44.0802031236-3.2585184342743.6727073931
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 27 through 45 )
2X-RAY DIFFRACTION2chain 'A' and (resid 46 through 80 )
3X-RAY DIFFRACTION3chain 'A' and (resid 81 through 135 )
4X-RAY DIFFRACTION4chain 'A' and (resid 136 through 153 )
5X-RAY DIFFRACTION5chain 'A' and (resid 154 through 167 )
6X-RAY DIFFRACTION6chain 'A' and (resid 168 through 214 )
7X-RAY DIFFRACTION7chain 'A' and (resid 215 through 228 )
8X-RAY DIFFRACTION8chain 'A' and (resid 229 through 240 )

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