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- EMDB-21646: IL-23 receptor complex -

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Basic information

Entry
Database: EMDB / ID: EMD-21646
TitleIL-23 receptor complex
Map dataIL-23 receptor complex
Sample
  • Complex: IL-23 receptor extracellular domain complex
    • Protein or peptide: Interleukin-23 receptor
    • Protein or peptide: Interleukin-23 subunit alphaInterleukin 23
    • Protein or peptide: Interleukin-12 subunit beta
    • Protein or peptide: Interleukin-12 receptor subunit beta-1
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 8.0 Å
AuthorsGlassman CR / Mathiharan YK / Panova O / Skiniotis G / Garcia KC
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)5R37AI051321 United States
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, 2020-
Header (metadata) releaseFeb 24, 2021-
Map releaseFeb 24, 2021-
UpdateMar 3, 2021-
Current statusMar 3, 2021Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.0234
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by radius
  • Surface level: 0.0234
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_21646.png

Downloads & links

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Map

FileDownload / File: emd_21646.map.gz / Format: CCP4 / Size: 15.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationIL-23 receptor complex
Voxel sizeX=Y=Z: 1.7 Å
Density
Contour LevelBy AUTHOR: 0.0234 / Movie #1: 0.0234
Minimum - Maximum-0.020516817 - 0.08236688
Average (Standard dev.)0.00010288022 (±0.003430682)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions160160160
Spacing160160160
CellA=B=C: 272.0 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.71.71.7
M x/y/z160160160
origin x/y/z0.0000.0000.000
length x/y/z272.000272.000272.000
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS160160160
D min/max/mean-0.0210.0820.000

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Supplemental data

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Sample components

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Entire : IL-23 receptor extracellular domain complex

EntireName: IL-23 receptor extracellular domain complex
Components
  • Complex: IL-23 receptor extracellular domain complex
    • Protein or peptide: Interleukin-23 receptor
    • Protein or peptide: Interleukin-23 subunit alphaInterleukin 23
    • Protein or peptide: Interleukin-12 subunit beta
    • Protein or peptide: Interleukin-12 receptor subunit beta-1

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Supramolecule #1: IL-23 receptor extracellular domain complex

SupramoleculeName: IL-23 receptor extracellular domain complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Details: IL-23 (IL-23p19,p40), IL-12Rb1 (with affinity enhancing Y109S and Q132L mutations), IL-23R
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
Molecular weightTheoretical: 153 kDa/nm

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Macromolecule #1: Interleukin-23 receptor

MacromoleculeName: Interleukin-23 receptor / type: protein_or_peptide / ID: 1
Details: hIL-23R (25-309), 3C protease site, Protein C tag, 8xHis
Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: ITNINCSGHI WVEPATIFKM GMNISIYCQA AIKNCQPRKL HFYKNGIKER FQITRINKTT ARLWYKNFLE PHASMYCTAE CPKHFQETLI CGKDISSGYP PDIPDEVTCV IYEYSGNMTC TWNAGKLTYI DTKYVVHVKS LETEEEQQYL TSSYINISTD SLQGGKKYLV ...String:
ITNINCSGHI WVEPATIFKM GMNISIYCQA AIKNCQPRKL HFYKNGIKER FQITRINKTT ARLWYKNFLE PHASMYCTAE CPKHFQETLI CGKDISSGYP PDIPDEVTCV IYEYSGNMTC TWNAGKLTYI DTKYVVHVKS LETEEEQQYL TSSYINISTD SLQGGKKYLV WVQAANALGM EESKQLQIHL DDIVIPSAAV ISRAETINAT VPKTIIYWDS QTTIEKVSCE MRYKATTNQT WNVKEFDTNF TYVQQSEFYL EPNIKYVFQV RCQETGKRYW QPWSSPFFHK TAAALEVLFQ GPGAAEDQVD PRLIDGKHHH HHHHH

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Macromolecule #2: Interleukin-23 subunit alpha

MacromoleculeName: Interleukin-23 subunit alpha / type: protein_or_peptide / ID: 2 / Details: IL23A (28-189) / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString:
PAWTQCQQLS QKLCTLAWSA HPLVGHMDLR EEGDEETTND VPHIQCGDGC DPQGLRDNSQ FCLQRIHQGL IFYEKLLGSD IFTGEPSLLP DSPVGQLHAS LLGLSQLLQP EGHHWETQQI PSLSPSQPWQ RLLLRFKILR SLQAFVAVAA RVFAHGAATL SP

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Macromolecule #3: Interleukin-12 subunit beta

MacromoleculeName: Interleukin-12 subunit beta / type: protein_or_peptide / ID: 3 / Details: IL12B (23-328), Biotin Acceptor Peptide, 6xHis / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: IWELKKDVYV VELDWYPDAP GEMVVLTCDT PEEDGITWTL DQSSEVLGSG KTLTIQVKEF GDAGQYTCHK GGEVLSHSLL LLHKKEDGIW STDILKDQKE PKNKTFLRCE AKNYSGRFTC WWLTTISTDL TFSVKSSRGS SDPQGVTCGA ATLSAERVRG DNKEYEYSVE ...String:
IWELKKDVYV VELDWYPDAP GEMVVLTCDT PEEDGITWTL DQSSEVLGSG KTLTIQVKEF GDAGQYTCHK GGEVLSHSLL LLHKKEDGIW STDILKDQKE PKNKTFLRCE AKNYSGRFTC WWLTTISTDL TFSVKSSRGS SDPQGVTCGA ATLSAERVRG DNKEYEYSVE CQEDSACPAA EESLPIEVMV DAVHKLKYEN YTSSFFIRDI IKPDPPKNLQ LKPLKNSRQV EVSWEYPDTW STPHSYFSLT FCVQVQGKSK REKKDRVFTD KTSATVICRK NASISVRAQD RYYSSSWSEW ASVPCSGRLH HILDAQKMVW NHRHHHHHH

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Macromolecule #4: Interleukin-12 receptor subunit beta-1

MacromoleculeName: Interleukin-12 receptor subunit beta-1 / type: protein_or_peptide / ID: 4 / Details: IL12RB1 (25-542) Y109S Q132L, 6xHis / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: RTSECCFQDP PYPDADSGSA SGPRDLRCYR ISSDRYECSW QYEGPTAGVS HFLRCCLSSG RCCYFAAGSA TRLQFSDQAG VSVLSTVTLW VESWARNQTE KSPEVTLLLY NSVKYEPPLG DIKVSKLAGQ LRMEWETPDN QVGAEVQFRH RTPSSPWKLG DCGPQDDDTE ...String:
RTSECCFQDP PYPDADSGSA SGPRDLRCYR ISSDRYECSW QYEGPTAGVS HFLRCCLSSG RCCYFAAGSA TRLQFSDQAG VSVLSTVTLW VESWARNQTE KSPEVTLLLY NSVKYEPPLG DIKVSKLAGQ LRMEWETPDN QVGAEVQFRH RTPSSPWKLG DCGPQDDDTE SCLCPLEMNV AQEFQLRRRQ LGSQGSSWSK WSSPVCVPPE NPPQPQVRFS VEQLGQDGRR RLTLKEQPTQ LELPEGCQGL APGTEVTYRL QLHMLSCPCK AKATRTLHLG KMPYLSGAAY NVAVISSNQF GPGLNQTWHI PADTHTEPVA LNISVGTNGT TMYWPARAQS MTYCIEWQPV GQDGGLATCS LTAPQDPDPA GMATYSWSRE SGAMGQEKCY YITIFASAHP EKLTLWSTVL STYHFGGNAS AAGTPHHVSV KNHSLDSVSV DWAPSLLSTC PGVLKEYVVR CRDEDSKQVS EHPVQPTETQ VTLSGLRAGV AYTVQVRADT AWLRGVWSQP QRFSIEVQAA AHHHHHH

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration1.04 mg/mL
BufferpH: 7.4
Component:
ConcentrationFormulaName
20.0 mMC8H18N2O4SHEPES
150.0 mMNaClSodium chlorideSodium Chloride
0.05 %C14H28O6octyl beta glucoside
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 200 / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 293 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal defocus max: 2.4 µm / Nominal defocus min: 1.5 µm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 44.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 488577
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 8.0 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Number images used: 33138
FSC plot (resolution estimation)

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